Compounds and methods for promoting smoking cessation

ABSTRACT

Compounds and methods for promoting smoking cessation. The compounds may be used to treat a variety of other conditions and disease states.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to methods and reagents for promotingsmoking cessation. The present invention relates to methods and reagentsfor preventing smoking addiction. The present invention also relates tomethods and reagents for treating nicotine addiction.

2. Background of the Invention

Smoking addiction is a complex phenomenon believed to involve cognitionenhancement, psychological conditioning, stress adaptation, reinforcingproperties and relief from withdrawal. Consequently, providingtherapeutic treatment for smoking addiction is an extremely difficultchallenge.

Tobacco products, including cigarettes, cigars, pipes and smokelesstobacco, can cause a variety of well-recognized health problems. From apublic health perspective, it is desirable to stop consuming tobaccoproducts, especially in the form of smoking. However, some individualscannot quit smoking tobacco products, in spite of focused attempts tosucceed. One major factor in the difficulty of quitting smoking is thepresence of nicotine in tobacco.

Nicotine can produce a myriad of behavioral effects and isunquestionably one of the most popular and powerful reinforcing agents.In addition, smoking, arguably the vehicle of choice for nicotinedelivery, may cause a variety of well-recognized health problems. Forthese reasons it has sometimes been desirable to cease consumption ofnicotine. However, for some, the termination of nicotine consumption cannot be accomplished, in spite of focused attempts to succeed.

One method for assisting smoking cessation is to reduce consumption overtime. For complex reasons, this method is not always entirelysuccessful. One method for assisting smoking cessation is to provide analternate delivery vehicle for nicotine. Such delivery vehicles includeoral preparations such as gums, and transdermal vehicles such as skinpatches.

Another method for assisting smoking cessation is to replace thenicotine signal from tobacco with a substitute reinforcer. Bupropion isused to promote smoking cessation and it may act as a substitutereinforcer.

Nicotine antagonists have been considered as an approach to smokingcessation. A nicotine antagonist would block the reinforcing signal fromnicotine that creates and maintains the addiction to smoking. Over time,the smoker would dissociate the physical and psychological aspects ofsmoking. For example, mecamylamine has been used to promote smokingcessation, although it is generally ineffective alone. Another approachis to administer an antagonist, e.g., mecamylamine, together withnicotine replacement therapy. Compounds which act as nicotinesubstitutes and block nicotine's effects would be preferred smokingcessation reagents.

In spite of the known methods for treating smoking addiction, thereremains a lack of generally effective means of treating and/orpreventing smoking addiction. Accordingly, there remains a strong needfor methods and reagents for treating smoking addiction.

Both the psychological and physiological effects of tobacco smoke areattributed to nicotine. Neuronal nicotinic acetylcholine receptors(nAChRs) are widely distributed throughout the central and peripheralnervous systems including several regions of the brain. Two majorclasses of nAChRs, α₄β₂ and α₇ have been identified in rat and humanbrains. The possibility exists that specific subtypes mediate specificfunctions, especially as this relates to nicotine addiction. Thus, theavailability of a variety of ligands that bind with high affinity andselectivity for each subtype are needed. It is also desirable to haveboth agonists and antagonists since the role of nAChRs in addiction isnot known.

Epibatidine is a nicotinic agonist whose biological effects appear to bemediated by α₄β₂ nAChRs. The high potency of epibatidine for α₄β₂ nAChRsmakes this agent a very useful lead compound for the development of newligands for studying this nicotinic subtype. Such epibatidine analogsmay be potent and/or selective for α₄β₂ receptors could provide atherapeutic for treatment of in addition to nicotine dependence, pain,and other neurological disorders.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide methods of traininga smoker to quit smoking.

It is another object of the invention to provide compounds which can beused to train a smoker to quit smoking.

It is an object of the present invention to provide a method of traininga smoker to quit smoking, comprising administering to a smoker in needthereof an effective amount of a compound represented by formula (I):

wherein

A₁ and A₂ are each, independently, H, —OH, —N(R)C(═NR)N(R)₂ or —N(R)₂;or

A₁ and A₂ together form ═O, ═NOR, ═NR, —O—NR—, —NR—O— or —NR—NR—;

each Q is, independently, C—X or N, with the proviso that at least one Qis N and at least one Q is C—X;

each X is, independently, H, halogen, alkyl, alkenyl, alkynyl, aryl,aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂,—NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN;

Y is a halogen; and

each R is, independently, H, alkyl, alkenyl, alkynyl, aryl, or aralkyl;

or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method oftraining a smoker to quit smoking, comprising administering to a smokerin need thereof an effective amount of a compound represented by formula(II):

wherein

A₃ is —R, —N(R)₂, —C(═NR)N(R)₂, or —OR; and

R and Q are as defined above,

or a pharmaceutically acceptable salt thereof.

It is also an object of the present invention to provide a method oftraining a smoker to quit smoking, comprising administering to a smokerin need thereof an effective amount of a compound represented by formula(III):

wherein

Z is —(CH₂)_(m)—, —O—, —NR—, —(CH₂)_(m)—O—, —O—(CH₂)_(m)—,—(CH₂)_(m)N(R)—, —N(R)(CH₂)_(m)—, —C(═NR)—, —(CH₂)_(m)S—,(CH₂)_(m)CH═CH—, or —(CH₂)_(m)C≡C—;

m is 1, 2, 3 or 4; and

R and Q are as defined above,

or a pharmaceutically acceptable salt thereof.

The present invention is also directed to the compounds represented byformula (I) and (III) above.

The present invention is also directed to the compounds represented byformula (II) above in which at least one Q group is C—X in which X isaryl.

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description.

BRIEF DESCRIPTION OF THE FIGURES

A more complete appreciation of the invention and many of the attendantadvantages thereof will be readily obtained as the same becomes betterunderstood by reference to the following detailed description whenconsidered in connection with the accompanying drawings, wherein:

FIG. 1 shows synthesis Scheme C1;

FIG. 2 shows synthesis Scheme C2;

FIG. 3 shows synthesis Scheme C3;

FIG. 4 shows synthesis Scheme C4;

FIG. 5 shows synthesis Scheme C5;

FIG. 6 shows synthesis Scheme D1;

FIG. 7 shows synthesis Scheme D2;

FIG. 8 shows synthesis Scheme D3;

FIG. 9 shows synthesis Scheme D4;

FIG. 10 shows synthesis Scheme D5;

FIG. 11 shows synthesis Scheme D6;

FIG. 12 shows synthesis Scheme 1;

FIG. 13 shows synthesis Scheme 2;

FIG. 14 shows synthesis Scheme 3;

FIG. 15 shows synthesis Scheme 4; and

FIG. 16 shows synthesis Scheme 5.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds represented by formula (I)-(III), each R or X may be,independently, alkyl, alkenyl, alkynyl, aryl, or aralkyl. The alkyl,alkenyl and alkynyl groups may have from 1 to 20 carbons atoms. Thealkenyl and alkynyl groups may have from 2 to 20 carbons atoms. The aryland aralkyl groups may have from 6 to 20 carbon atoms. These rangesinclude all specific values and subranges therebetween, such as 2, 4, 8,10 and 12 carbon atoms. A preferred aryl group is phenyl. Preferredaralkyl groups include benzyl and phenethyl groups. The groups describedabove may be unsubstituted or substituted.

When R or X is aryl or aralkyl, the substituent is preferablyrepresented by the formula:

where k is 0, 1, 2, 3 or 4, and S and c are as defined below.

In one embodiment of the present invention, R, X or S is a substitutedalkyl group represented by the formula —(CH₂)_(n)—Y, where Y is ahalogen and n is an integer from 1 to 8. In addition, X may also be ahalogen. Examples of suitable halogens include —F, —Cl, —Br and —I.

Each Q is, independently, C—X or N, provided that at least one Q is Nand at least one Q is C—X. Preferably, up to three Q are N. Morepreferably, up to two Q are N. Most preferably, one Q is N.

As described above, when not N, Q is C—X. In a preferred embodiment ofthe invention, one, two, or three X may be other than hydrogen, asdefined above.

In a preferred embodiment of the invention, at least one X is asubstituted or unsubstituted aryl group. Phenyl is a preferred arylgroup. Suitable substituents include one or more of the following:halogen (e.g., F, —Cl, —Br and —I), alkyl, alkenyl, alkynyl, aryl,aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂,—NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY or —CN, where R is as definedabove. Particularly preferred substituents for the aryl group includehalogen, especially —F and —Cl, alkyl, especially methyl, and alkoxy,especially methoxy. The substituted aryl group preferably has one or twosubstituents. In a particularly preferred embodiment, one Q is N and oneX is a substituted or substituted aryl group.

As one skilled in the art will readily appreciate, compounds of formula(I)-(III) in which an alkenyl or alkynyl group is attached to aheteroatom, e.g., N or O, there is no double or triple bond between theheteroatom and the carbon atom of the alkenyl or alkynyl group that isdirectly bonded to the heteroatom.

In formula (I), A₁ and A₂ are each, independently, H, —OH,—N(R)C(═NR)N(R)₂ or —N(R)₂. Preferably, at least one of A₁ and A₂ are—OH, —N(R)C(═NR)N(R)₂ or —N(R)₂, or A₁ and A₂ together form —O, —NOR,—NR, —O—NR—, —NR—O—, or —NR—NR—.

The compounds are illustrated with the group A₃ of undefinedstereochemistry in formula (II), such that the A₃ group may be on theopposite or same side of the bridging nitrogen as the ring substituent.

Preferred compounds of formula (I) are represented by formula (Ia):

where A₁ and A₂ are as defined above and X₁, X₂, X₃ and X₄ are asdefined for X above.

Additional preferred compounds of formula (I) are represented by formula(Ib) below:

where A₁ and A₂ are as defined above, X₁, X₂, X₃ and X₄ are as definedfor X above, and S and c are as defined below.

Preferred compounds of formula (II) are represented by formula (IIa):

where A₃ is defined above, and X₁, X₂, X₃ and X₄ are as defined for Xabove.

Particularly preferred compounds of formula (IIa) are those in which X₂is unsubstituted or unsubstituted aryl, more preferably unsubstituted orunsubstituted phenyl, When substituted, the phenyl group have one ormore substituents selected from the group consisting of halogen, alkyl,alkenyl, alkynyl, aryl, aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R,—N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHYand —CN. Particularly preferred substitents in include —NO₂ and —OCH₃.In these compounds, it is preferable that X₃ and X₄ are both H.

Even more particularly preferred compounds of formula (II) are thoserepresented by formula (IIb):

where

each S is, independently, halogen, alkyl, alkenyl, alkynyl, phenyl,aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂,—NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY or —CN, or

two S, taken together with the phenyl group to which they are bonded,form a 2-naphthyl group.

c is 0, 1, 2, 3, 4 or 5; and

A₁, X₁, X₃, X₄ and R are as defined above.

Preferred examples of alkenyl and alkynyl substituents as S includeCR_(z)═CR_(z)R_(z), CR_(z)R_(z)—CH═CR_(z)R_(z), C≡CR_(z),C(═R_(z)R_(z))R_(z), where each R_(z) is, independently, H, C₁₋₆ alkyl,phenyl, substituted phenyl, CH₂OH, or C₁₋₆-phenyl.

As noted above, c may be 0, in which case the phenyl ring isunsubstituted. When the phenyl ring is substituted, c is preferably 1, 2or 3.

This phenyl group, optionally substituted by one to five S substituents,may be present at any of the other positions of the ring defined by theQ's. In addition, this phenyl group may be present in any of thecompounds represented by formula (I), (II) or (III), at any position ofthe ring defined by the Q's.

Preferred compounds of formula (III) are represented by formula (IIIa)or (IIIb):

where Z is as defined above, and X₁, X₂ and X₃ are as defined for Xabove.

The compounds depicted as above are shown as a single enantiomericcompound, however, both enantiomers are within the scope of the presentinvention, such as a racemic mixture. Moreover, it is within thespecific scope of the present invention to administer compounds whichare enantiomerically enriched in a single enantiomer. Within the contextof the present invention enrichment in a single enantiomer may comprisean enantiomeric excess (e.e.) of ≧55%, even more preferably ≧70%, evenmore preferably ≧80%, even more preferably ≧90%, even more preferably≧95%, even more preferably ≧98%.

An enantiomerically enriched composition may be prepared by conventionalmethods known to those of ordinary skill in the art, such as by using anenantiomerically enriched starting material or by resolution of aracemic mixture or a mixture of a lower enantiomeric purity. Resolutionmay be conducted by conventional methods known to those of skill in theart, such as by chiral chromatography, formation of diasteriomericderivatives followed by separation, or enantioselective crystallization.

The compounds may be used in the form of a pharmaceutically acceptablesalt via protonation of the amine with a pharmaceutically acceptableacid. The acid may be an inorganic acid or an organic acid. Suitableacids include, for example, hydrochloric, hydroiodic, hydrobromic,sulfuric, phosphoric, citric, acetic and formic acids.

Administration of the Compounds

A variety of administration techniques may be utilized, among them oral,transdermal or parenteral techniques such as subcutaneous, intravenous,intraperitoneal, intracerebral and intracerebroventricular injections,catheterizations and the like. Such methods of administration arewell-known to those skilled in the art. For a general discussion of drugdelivery systems, see Kirk-Othmer Encyclopedia of Chemical Technology,Fourth Edition, Volume 8, pp. 445-475.

Average quantities of the compounds may vary in accordance with thebinding properties of the compound (i.e., affinity, onset and durationof binding) and in particular should be based upon the recommendationsand prescription of a qualified physician.

The therapeutic compositions useful in practicing the therapeuticmethods of this invention may include, in admixture, a pharmaceuticallyacceptable excipient (carrier) and one or more of the compounds of theinvention, as described herein as an active ingredient.

The preparation of therapeutic compositions which contain suchneuroactive compounds as active ingredients is well understood in theart. Such compositions may be prepared for oral administration, or asinjectables, either as liquid solutions or suspensions, however, solidforms suitable for solution in, or suspension in, liquid prior toinjection can also be prepared. The preparation can also be emulsified.The active therapeutic ingredient is often mixed with excipients whichare pharmaceutically acceptable and compatible with the activeingredient. Suitable excipients are, for example, water, saline,dextrose, glycerol, ethanol, or the like and combinations thereof. Inaddition, if desired, the composition can contain minor amounts ofauxiliary substances such as wetting or emulsifying agents, and pHbuffering agents which enhance the effectiveness of the activeingredient. The compounds of the invention can be formulated into thetherapeutic composition as neutralized pharmaceutically acceptable saltforms.

The therapeutic compositions are conventionally administered orally, byunit dose, for example. The term “unit dose” when used in reference to atherapeutic composition of the present invention refers to physicallydiscrete units suitable as unitary dosage for humans, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect in association with the requireddiluent; i.e., carrier, or vehicle.

The compositions are administered in a manner compatible with the dosageformulation, and in a therapeutically effective amount. The quantity tobe administered depends on the subject to be treated, the presence ofother agonists and antagonists in the subject's system, and degree ofbinding or inhibition of binding desired. Precise amounts of activeingredient required to be administered depend on the judgment of thepractitioner and are peculiar to each individual. However, suitabledosages may range from about 0.01 to about 1,000, preferably about 0.25to about 500, and more preferably 10 to 50 milligrams of activeingredient per kilogram body weight of individual per day and depend onthe route of administration. For oral administration, 1 to 100milligrams of active ingredient per kilogram body weight of individualper day is a preferred dose. However, the exact dosage must bedetermined by factoring in rate of degradation in the stomach,absorption from the stomach, other medications administered, etc.Suitable regimes for administration are also variable, but are typifiedby an initial administration followed by repeated doses at one or morehour intervals by a subsequent injection or other administration.Alternatively, continuous intravenous infusion sufficient to maintainappropriate concentrations in the blood are contemplated.

The present invention is directed to a method of treating smokingaddiction. This may be accomplished by administering a compound of thepresent invention to a patient in need of terminating a smokingaddiction. While not wishing to bound by any particular theory, it isbelieved that by smoking addiction may be successfully treated byblocking some of the pharmacological effects of nicotine, such as, butnot limited to reinforcement, antinociception, hypothermia, drugdiscrimination and motor impairment, while also dissociating some of thereinforcing affects of smoking. Within the context of the presentinvention, a patient in need of terminating a smoking addiction is aperson who smokes on a regular basis and is either unable or unwillingto terminate smoking on a regular basis. The method of treating asmoking addiction may be practiced, by administering the compound of thepresent invention as described, preferably concurrent with or in advanceof the act of smoking. In this fashion, the patient addicted to smokingwill also be subject to the effects of the compounds while smoking,which can act to dissociate the reinforcing effects of smoking, from theact of smoking itself. The amount of the compound administered to beeffective to dissociate the reinforcing effects of smoking from the actof smoking may vary depending on the patient and the nature of thepatients addiction to smoking, however, determination of effectivedosages and treatment schedules is within the level of skill of those ofordinary skill in the art, without undue experimentation.

The present invention is also directed to a method of preventing anaddiction to smoking, by administering a compound of the presentinvention. A person (patient) in need of preventing an addiction tosmoking may be a non-smoker or an occasional smoker, who is concernedabout developing an addiction to smoking. The method of preventing asmoking addiction may be practiced, by administering the compounds asdescribed, preferably in advance of the act of smoking. In this fashion,subject to the effects of the phenyltropane compounds, the patient willnot develop a strong association of the act of smoking with thereinforcing effects of smoking. The amount of compound administered tobe effective to prevent the association of the reinforcing effects ofsmoking from the act of smoking may vary depending on the patient andthe nature of the patient. However, determination of effective dosagesand treatment schedules is within the level of skill of those ofordinary skill in the art, without undue experimentation.

The present invention is also directed to a method of treating nicotineaddiction. This may be accomplished by administering a compound of thepresent invention to a patient in need thereof. Within the context ofthe present invention, a patient in need of terminating a nicotineaddiction is a person who consumes nicotine on a regular basis and iseither unable or unwilling to terminate nicotine consumption on aregular basis. The method of treating a nicotine addiction may bepracticed, by administering compounds as described, preferablyconcurrent with or in advance of the act of nicotine consumption. Inthis fashion, the patient addicted to nicotine will also be subject tothe effects of the phenyltropane compounds, which can act to dissociatethe physiological effects of nicotine consumption from the act ofconsuming nicotine. The amount of compound administered to be effectiveto dissociate the physiological effects of nicotine from the act ofnicotine consumption may vary depending on the patient and the nature ofthe patients addiction to nicotine. However, determination of effectivedosages and treatment schedules is within the level of skill of those ofordinary skill in the art, without undue experimentation.

The effectiveness of the present method is appreciated in the ability toblock some but not all of the pharmacological effects of nicotine. In apreferred embodiment the present method blocks the pharmacologicaleffects of antinociception, seizures, and motor impairment, while noteffecting body temperature or drug discrimination.

According to another embodiment of the present invention, it is possibleto prevent the development of an addiction to smoking, by administeringto a human in need of preventing an addiction to smoking, a compound. Inthis embodiment, the compound can be administered prophylactically inorder to prevent a subject from becoming addicted to smoking in thefirst place. Alternatively, the compound can be administered to asubject who is in the process of smoking cessation in order to prevent arelapse.

Other Pharmacological Uses of the Compounds of the Present Invention

In addition for their use in smoking cessation as described above, thecompounds of the present invention, by virtue of the function asnicotinic ligands, may be used to treat other disease states. Examplesof such conditions include Alzheimer's disease, Parkinson's disease,pain (analgesic activity), depression, Tourette's syndrome, inflammatorybowel syndrome, schizophrenia, anxiety, epilepsy, attention-deficithyperactivity disorder, ulcerative colitis and obesity. Thus, thecompounds of the present invention may be administered to a patient inneed thereof, e.g., a human, in an amount effective to treat thesedisease states. As will be readily appreciated, the amount of compoundadministered to be effective for each disease state may vary dependingon the patient and the nature of the patients addiction to nicotine.However, determination of effective dosages and treatment schedules iswithin the level of skill of those of ordinary skill in the art, withoutundue experimentation. The dosage may range from 0.01 to 1000,preferably from about 0.25 to about 500 milligrams of the compound perkilogram of patient body weight per day, depending on the route ofadministration. The compounds may be administered as described above forsmoking cessation.

Imaging and Tracer Applications

Appropriately labeled compound represented by formula (I)-(III) may beuseful in a variety of variety of applications. For example, the labeledcompounds may be used for imaging drug and neurotransmitter receptors byPET or SPECT. The labeled compounds may also be useful in ligand bindingassays. Since little is known about the in vivo disposition of nAChRsboth before and after chronic nicotine exposure, such labeled compoundswould be very useful in the study of nAChRs. The labeled compounds ofthe present invention may be useful radio-labeled ligands for imagingthe nicotinic receptor in vivo by PET or SPECT.

For use in imaging and tracer applications, the compounds of the presentinvention may be labeled with any detectable label. Accordingly, thepresent invention includes compounds of represented by formula (I)-(III)which are labeled with at least one labeling atom. Preferably, the labelis a radioactive element. Examples of suitable radioactive elementsinclude ³H, ¹¹C, ¹⁴C, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ⁵¹Cr, ⁵⁷Co, ⁵⁹Fe, ⁹⁰Y, ¹²³I,¹²⁵I, and ¹³¹I. Preferred radioactive elements include ³H, ¹¹C, ¹⁸F,¹²³I. Specific examples of suitable labeled compounds are those where atleast one X is ¹⁸F, ¹²³I, ¹²⁵I or ¹³¹I, or X is a phenyl groupsubstituted with one or more of ¹⁸F, ¹²³I, ¹²⁵I or ¹³¹I. One skilled inthe art will also appreciate that the labeled compound may berepresented by formula (I)-(III) in which one or more hydrogen atom inthe formula is replaced with ³H and/or one or more carbon atoms isreplaced with 11C and/or ¹⁴C. A specific example of a labeled compoundof the present invention is the 2′-fluoro analog C1b, see below, labeledwith fluorine-18. This compound has been demonstrated to be useful inmapping nicotinic receptors by PET.

Synthesis of Compounds

Synthetic routes for the preparation of compounds of within the scope ofthe present invention are set forth in the synthetic schemes shown inFIGS. 1-16. Specific examples of synthetic procedures are provided inthe Examples below.

The compounds represented by formula (I)-(III) may be prepared from, forexample, 7-(tert-butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene (C4b).The preparation of (C4b) is shown in Scheme C1 (FIG. 1) described below.

Olefin (C3a) shown in Scheme C1 can be obtained in two steps fromp-tolylsulfonylacetylene and N-(methoxycarbonyl)pyrrole as described byClayton and Regan, Tetrahedron Letters, vol. 34, no. 46, pp. 7493-7496,1993, incorporated herein by reference. As shown in Scheme C1 (FIG. 1),removal of the p-tolylsulfonyl from C3a to give C4a was achieved usingsodium amalgam. Clayton and Regan reported that palladium-catalyzedreductive addition of 2-chloro-5-iodopyridine (C5) to C4a gaveexclusively the desired 2-exosubstituted compound C6 which yielded C1aon treatment with hydrogen bromide in acetic acid. It has been foundthat reductive palladium-catalyzed addition of C4b using2-amino-5-iodopyridine (C7) afforded exclusively the7-(tert-butoxycarbonyl)-exo-2-(2′-amino-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane(C8) (Liang 1997). Importantly, this intermediate is highly useful forpreparing many of the compounds of the present invention. Epibatidine(C1a) was obtained in better overall yield and purity by diazotizationof C8 followed by treatment with cuprous chloride in hydrochloric acid.It is preferred that freshly prepared sodium amalgam be used to convertC3a and C3b to the olefins C4a and C4b, respectively. 2.5% sodiumamalgam was used for the preparation of C4b, where over 2 kg wasrequired to synthesize 10 g of C4b.

A higher yield synthesis of C4b that can be easily upscaled to providelarge amounts of this compound is shown in Scheme C1 (FIG. 1). Theaddition of tributyltin hydride to C3b in benzene containing2,2′-azabisisobutyronitrile (AIBN) gave 78-91% of C9 depending on thescale (0.04 to 0.07 mol). Treatment of C9 with tetrabutylammoniumfluoride in tetrahydrofuran provides 93-98% of C4b that was identical tomaterial prepared using sodium amalgam (Brieaddy et al 1998). The readyavailability of C4b provides for the synthesis of many compounds withinthe scope of the present invention.

As shown in Scheme C2 (FIG. 2), compound C8 was used to prepare racemicepibatidine (C1a) as well as the compounds C1b-i. Diazotization of C8using sodium nitrite in hydrochloric acid containing either cuprouschloride, pyridine containing 70% hydrogen fluoride, hydrogen bromidecontaining bromine, or acetic acid containing potassium carbonate gaveepibatidine (C1a), the 2′-fluoro and 2′-bromo analogs C1b and C1c, andthe N-tert-butoxycarbonyl 2′-hydroxy compound C11, respectively.Treatment of C11 with trifluoromethanesultonic anhydride gave the2′-triflate C12. Diazotization of C8 with isoamylnitrite in methyleneiodide containing hydrogen iodide afforded the N-tert-butyloxycarbonyl2′-iodo compound C10. Reductive methylation of C8 with formaldehydeusing sodium cyanoborohydride yielded the N-tert-butoxycarbonyl2′-dimethylamino analog C13. Treatment of C8 and C10-C13 withtrifluoroacetic acid yielded compounds C1d-h. Reductive dehalogenationof C1a gave the unsubstituted analog C1i. Compound C1i can also beprepared by adding 3-iodopyridine to C4b under reductive Heck conditionsfollowed by treatment with trifluoroacetic acid (FIG. 2).

Both 3-amino-2-fluoro-5-iodopyridine and 3-amino-2-chloro-5-iodopyridine(Woolard et al. 1997) add to the olefin C4b to give the expected 2-exoaddition products C14 and C15, respectively (Scheme C3, FIG. 3).Reductive dehalogenation of C14 gives the 3-amino compound C16.Diazotization of C14, C15, and C16 using sodium nitrite in hydrochloricacid containing cuprous chloride yielded C17, C18, and C19,respectively.

Bromination of C8 affords the 2-amino-3-bromo compound C20 (Scheme C4,FIG. 4). Palladium acetate catalyzed reaction of C20 with phenylboronicacid in dimethoxyethane (DME) in the presence of tri-(2-tolyl)phosphinegave the 2-amino-3-phenyl compound C21. Diazotization of C20 usingsodium nitrite in hydrogen bromide containing bromine afforded C22.Diazotization of C21 using sodium nitrite in hydrochloric acidcontaining cuprous chloride gave C23. Diazatization of C21 using sodiumnitrite in pyridine HF afforded C23a. Treatment of C21 withtrifluoroacetic acid yielded C24.

Scheme C5 (FIG. 5) shows the synthesis of a compound in which the7-norbornane substructure in epibatidine is modified. The addition of2-amino-5-iodopyridine to 7-hydroxynorbornane (C25) (Story 1961) usingconditions analogous to those we used for C4b gave the exo product C26.Diazotization of C26 using sodium nitrite in hydrochloric acidcontaining cuprous chloride afforded the 2-chloro compound C27.Oxidation of C27 using dimethylsulfoxide in the presence of pyridinesulfur trioxide complex and triethylamine yielded the 7-keto analog C28.Reductive amination of C28 using benzylamine and sodium cyanoborohydridein methanol gave C29 (the structure was established using ¹H NMR methodsincluding nOe effects). Reductive debenzylation using ammonium formateand 10% palladium-on-carbon in methanol yielded the desired C30.

Intermediates for the syntheses of the compounds of the presentinvention include7-tert-butyloxycarbonyl-exo-2-(2′-amino-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane(C8),7-tert-butyloxycarbonylexo-2-(3′-amino-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane(C16),7-tert-butyloxycarbonyl-exo-2-(3′-amino-2′-chloro-5′-pyridinyl)-7-azabicyclo[2.2.1]heptane(C14),7-tert-butyloxycarbonyl-exo-2-(3′-amino-2′fluoro-5′pyridinyl)-7-azabicyclo[2.2.1]heptane(C15), and7-tert-butyloxycarbonyl-exo-2-(2′-amino-3′-bromo-5′pyridinyl)-7-azabicyclo[2.2.1]heptane(C20). The syntheses of C8, C14, C15, C16, and C20 have been describedabove.

The syntheses of the 3′-substituted compounds T2a-h starting with C16are shown in Scheme D1 (FIG. 6). Below the compounds T1a-e and T2i-kwill be prepared from C8 or C16 as outlined in Scheme D2 (FIG. 7). BelowDiazotization of C8 followed by treatment with sodium azide or potassiumcyanide gives the 2-azido and 2′-cyano target compounds T1a and T1b,respectively. Acylation of C8 or C16 with acetic anhydride propionicanhydride of phenyl formate yields T1c or T2i, T1d or T2j, T1e or T2k,respectively, depending on the starting amino compound.

Scheme D3 (FIG. 8) shows a synthetic route for T3a-f, T4a-f, D3.4, D3.5and D3.6 starting with C20. Diazotization of C20 using sodium nitrite inpyridine-hydrogen fluoride, hydrochloric acid containing cuprouschloride, hydrogen bromide containing bromine, or acetic acid containingpotassium carbonate will give T3b-d and the 2′-hydroxy compound D3.2,respectively. Diazotization of C20 with isoamylnitrite in methyleneiodide containing hydrogen iodide will give the N-tert-Boc-2′-iodocompound D3.1. Treatment of C20, D3.1, and D3.2 with trifluoroaceticacid affords the target compounds T3a, T3e, and T3f, respectively.Palladium-catalyzed coupling of C20 with the appropriate aryl boronicacid, which is either commercially available or can be prepareddirectly, will give D3.3. Treatment of D3.3 (X=H, Y=NO₂) withtrifluoroacetic acid gives D3.4. Diazotization of the appropriate D3.3intermediate in hydrochloric acid containing cuprous chloride, hydrogenbromide containing bromine or isoamylnitrate containing methylene iodidewill yield the desired target compounds T4a-j, D3.5 and D3.6.

The synthesis of compounds T3g-n, shown in Scheme D4 (FIG. 9), followsthe same course used to prepare similar compounds. In this case, thestarting intermediates are C14 and C15.

The compounds T1f-m and T2l-m may be prepared by procedures analogous tothose that used to prepare similarly substituted 3B-phenyltropaneanalogs (Blough et al. 1996; McKean et al. 1987; Knochel and Singer1993; Sonogashira et al. 1975; Echavarren and Stille 1987; Rossi andBaellina 1997; Haack et al. 1988). The methods are shown in Scheme D5(FIG. 10).

Scheme D6 (FIG. 11) outlines methods to prepare the target compoundsT5-T10. Diazotization of C26 followed by treatment with hydrogenchloride-cuprous chloride, pyridine-hydrogen-fluoride, hydrogenbromide-bromine will give C27, D6.1, and D6.2, respectively. Oxidationwith dimethylsulfoxide in the presence of pyridine sulfur trioxidecomplex and triethylamine will yield the ketones C28, D6.3, and D6.4.Reductive amination of these intermediates using ammonia in methanol andsodium cyanoborohydride followed by separation in each case will givethe target compounds T5a-c and T6a-c. Treatment of C28, D6.3, and D6.4with hydroxylamine-O-sulfonic acid in the presence of ammonium hydroxidewill yield the diaziridines T8a-c (Schmitz and Ohme 1965). Theoxaziridines T9a-c and T10a-c can be prepared by the reaction ofhydroxylamine-O-sulfonic acid with C28, D6.3, and D6.4, respectively,followed by separation in each case (Schmitz et al 1964). Treatment ofepibatidine (C1a), C1b, and C1c with hydroxylamine-O-sulfonic acid willgive the hydrazine T7a-c (Gosland and Meuwsen 1963).

FIG. 12 (Scheme 1) outlines the synthetic methods used to prepare thecyclic analogs, 7, 8, and 9, shown in this Scheme. Iodination of 1 usingiodine in a periodic acid, sulfuric acid, acetic acid mixture afforded2-amino-5-iodo-4-picoline (2). Reaction of 2 with meta-chloroperbenzoicacid in acetone gave the N-oxide 3. Treatment of an ethereal solution of3 with acetic acid containing hydrogen chloride provided4-acetamido-4-chloromethyl-5-iodopyridine (4) alkylation of azabicycloolefin 5 with 4 gave the tert-amine 6. Intramolecular cyclization of 6using reductive Heck conditions [Pd(OAc)₂, KO₃CH, Bu₄N⁺Cl, DMF] yieldedthe cyclic analog 7. Hydrolysis of 7 using 3N hydrochloric acid affordedthe amino compound 8, which yielded the chloro analog 9 when treatedwith sodium nitrite in concentrated hydrochloric acid. Compounds 15, 16,and 17 were synthesized by an analogous set of reactions starting with2-amino-picoline (FIG. 13, Scheme 2).

Representative synthetic procedures for preparing compounds of thepresent invention are described in Scheme 1, 2, 3, 4 and 5 shown inFIGS. 12, 13, 14, 15 and 16, respectively. The procedures are describedin more detail in the following Examples.

As one will readily appreciate, the synthetic routes described in FIGS.1-16 and the more detailed procedures set forth in the followingExamples can be readily adapted to other compounds represented byformula (I), (II) or (III).

EXAMPLES

Having generally described this invention, a further understanding canbe obtained by reference to certain specific examples which are providedherein for purposes of illustration only and are not intended to belimiting unless otherwise specified.

Table 1 and 2 below present epibatidine binding assay data for compoundsrepresented by formula (I)-(III). The binding assay data reported in theTables was obtained according to the procedure described below.

Epibatidine Binding Assay

Adult male rat cerebral cortices (Pelfreeze Biological, Rogers, Ark.)were homogenized in 39 volumes of ice-cold 50 mM Tris buffer (pH 7.4 at4° C.) containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂ and 1 mM MgCl₂ andsedimented at 37,000×g for 10 minutes at 4° C. The supernatant wasdiscarded and the pellet resupended in the original volume of buffer andthe wash procedure repeated twice more. After the last centrifugation,the pellet was resuspended in {fraction (1/10)} its originalhomogenization volume and stored at −80° C. until needed. In a finalvolume of 0.5 mL, each assay tube contained 3-6 mg wet weight male ratcerebral cortex homogenate (added last), 0.5-2 nM [³H]Epibatidine (NENLife Science Products, Wilmington, Del.) and one of 10-12 differentconcentrations of test compound dissolved in buffer (pH 7.4 at RT)containing 10% DMSO. Total and nonspecific binding were determined inthe presence of vehicle and 300 uM (−)nicotine, respectively. After afour-hour incubation at room temperature, the samples werevacuum-filtered over GF/B filter papers presoaked in 0.03%polyethylenimine using a Brandel 48-well or a Packard MultiMate 96-wellharvester and washed with 3-6 mL of ice-cold buffer. The amount ofradioactivity trapped on the filter was determined by standard liquidscintillation techniques in a TriCarb 2200 or TopCount scintillationcounter (both from Packard Instruments, Meriden, Conn.) at approximately50 or 37% efficiency, respectively. The binding data were fit using thenonlinear regression analysis routines in Prism (Graphpad, San Diego,Calif.). The K_(i) values for the test compounds were calculated fromtheir respective IC₅₀ values using the Cheng-Prusoff equation.

TABLE 1 Radioligand Binding Data

α₄β₂ RTI- [³H]Epibatidine 7527- Compound Structure X₁ X₂ X₃ X₄ R₁ R₂(K_(i), nM) Hill Slope (±)-EB — — — H — — — — (+)-EB H — — 0.026 0.98 ±0.05  (−)-EB H — — 0.018 ± 0.001 1.02 ± 0.07  1 B Cl H H H ═NOH >1000 2B Cl H H H ═NOCH₃ >1000 3 B Cl H H H H NH₂  8.2 ± 0.08 1.2 ± 0.04 4 A ClH CH₃ H — — 17.2 ± 2.2  1.1 ± 0.05 5 A Cl H H CH₃ — — 256 ± 74  1.1 ±0.03 13 A F H H — — 0.027 ± 0.001 0.9 ± 0.02 14 A NH₂ H H — — 0.027 0.001 15 A H H H — —  0.02 ± 0.001 0.8 ± 0.02 16 A Br H H H — — 0.023 ±0.001 0.9 ± 0.03 17 A CF₃SO₃ H H H — — 8.5 ± 0.2 1.1 ± 0.02 18 A OH H HH — —  107 ± 0.5  1.0 ± 0.05 19 A (CH₃)₂N H H H — — 26.4 ± 1.4  1.0 ±0.01 20 A F Br H H — — 0.071 ± 0.005 0.98 ± 0.01  21 A I Br H H — —0.027 ± 0.002 0.96 ± 0.05  22 A Cl Br H H — — 0.013 ± 0.001 0.95 ± 0.09 23 A NH₂ Br H H — — 0.29 ± 0.01 1.0 ± 0.03 24 A NH₂ I H H — — 1.47 ±0.12 1.07 ± 0.14  25 A Br Br H H — —  0.015 ± 0.0005 0.90 ± 0.02  26 ACl C₆H₅ H H — — 0.021 ± 0.005 0.81 ± 0.02  27 A I C₆H₅ H H — — 0.019 ±0.002 0.84 ± 0.02  28 A NH₂ C₆H₅ H H — — 0.33 ± 0.05 0.93 ± 0.03  29 AOH C₆H₅ H H — — 51.9 ± 2.0  1.04 ± 0.07  30 A Cl I H H — —  0.012 ±0.0003 0.83 ± 0.03  31 A Cl F H H — —  0.021 ± 0.0006 0.86 ± 0.02  32 ACl Cl H H — — 0.015 ± 0.001 0.87 ± 0.04  33 A Cl NH₂ H H — —  0.011 ±0.0003 0.90 ± 0.04  34 A OH Br H H — — 35.5 ± 5.4  1.08 ± 0.03  35 A HCl H H — —  0.12 ± 0.006 0.9 ± 0.03 36 A H F H H — — 0.037 ± 0.001 0.9 ±0.01 37 A F Cl H H — —  0.020 ± 0.0003  0.8 ± 0.004 38 A F F H H — —0.055 ± 0.001 1.0 ± 0.01 39 A F I H H — — 0.076 ± 0.004 1.0 ± 0.05 40 AH NH₂ H H — — no data 41 A H I H H — — 0.059 ± 0.001 0.9 ± 0.02 42 A NH₂3NO₂C₆H₄ H H — — 0.047 ± 0.002 1.1 ± 0.09 43 A Cl 3NO₂C₆H₄ H H — — 0.008 ± 0.0003 0.9 ± 0.10 44 A Br 3NO₂C₆H₄ H H — — 0.005 ± 0.001 0.7 ±0.04 45 A Cl 3CH₃OC₆H₄ H H — — 0.019 ± 0.005 0.8 ± 0.02 46 A H 3CH₃OC₆H₄H H — — 0.43 ± 0.05 0.9 ± 0.03 47 A F C₆H₅ H H — — 0.14 ± 0.07 1.1 ±0.04 48 A (CH₃)₂N C₅H₅ H H — — 50.2^(a) 1.03 49 B OH H H H H H 1270^(A)1.1  50 B Cl H H H HO H >1000 α₄β₂ RTI- [³H]Epibatidine 7527- StructureX₁ X₂ Z X₄ R₁ R₂ (K_(i), nM) Hill Slope 51 B Cl H H H H OH >1000 52 BNH₂ H H H HO H 19,000^(a) 1.2  53 B Cl H H H ═O >1000 54 B NH₂ H H H H H   2200^(a) 1.1  55 B H H H H H NH₂ 9.6 ± 2  0.93 ± 0.03  56 B Cl H H HH C₆H₅CH₂NH   2200^(a) 1.1  57 B Cl H H H C₆H₅CH₂NH H >1000

TABLE 2 Radioligand Binding Data

α₄β₂ [³H]Epibatidine RTI-7527- Structure X (K_(i), nM) Hill Slope 6 ANH₂  7370 ± 1240  1.1 ± 0.03 7 A Cl 1260 ± 400 0.92 ± 0.06 8 B Cl 3330 ±310 0.99 ± 0.08 9 B NH₂ 12,400 ± 860   0.87 ± 0.03 10 B NHAc 9030 ± 3100.85 ± 0.04 11 C Cl  22.8 ± 0.001 1.07 ± 0.05

SYNTHETIC EXAMPLES Experimental Procedures for Scheme C3 Shown in FIG. 32-exo-[5′-(3′-Amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Amino-2′-fluoropyridinyl)]7-azabicyclo[2.2.1]-heptane(45 mg, 0.146 mmol) in methylene chloride (3.0 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (1.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa solution of 1:1 NH₂OH:H₂O and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography using 90 CMA aseluent to give2-exo-[5′-(3′-Amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (20mg, 66%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.35-1.8 (m, 5H), 1.87 (dd, J=9.0, 12.0 Hz, 1H),2.70 (dd, J=5.2, 9.0 Hz, 1H), 3.53 (br s, 2H), 3.60 (br s, 1H), 3.76 (brs, 3H), 7.20-7.29 (m, 1 pyridyl CH), 7.89 (s, 1 pyridyl CH); ¹³C NMR(CDCl₃) δ (ppm) 29.94, 31.27, 40.39, 44.33, 56.31, 62.77, (morecomplicated fluorine splittings).

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane

To a stirred mixture of 138 mg of7-tert-butoxycarbonyl-7-azabicyclo[2,2,1]-heptene (0.704 mmol), 157 mgof 2-fluoro-5-iodopyridine (0.704 mg), 196 mg of n-Bu₄NCl (0.704 mmol),89 mg of KO₂CH (1.06 mmol) in 1.0 mL of DMF at room temperature undernitrogen was added 16 mg of Pd(OAc)₂ (0.07 mmol). After 4 days, thereaction mixture was diluted with 50 mL of 25% ethyl acetate in hexanes,filtered through an 1 inch pad of celite, concentrated under reducedpressure to give 150 mg of a yellow oil. This material was purified withchromatatron eluting with 10% (CHCl₃:CH₃OH:NH₄OH/40:9:1) in CH₂Cl₂ togive 106 mg of 7-tert-butoxycarbonyl-2-exo-[59-(2′-fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (51%) as a colorlessoil.

¹H NMR (CDCl₃) δ (ppm) 1.34-1.71 (m. 3H),1.36 (s, 9H) 1.93 (dd, J=9.0,12.3, 1H), 2.81 (dd, J=5.0, 9.0, 1H), 4.08 (m, 1H), 4.30 (m, 1H), 6.78(dd, J=3.0, 8.5, 1H), 7.70 (ddd, J=2.2, 8.5, 8.5, 1H), 7.99 (d, J=2.2,1H); ¹³C NMR (CDCl₃) δ (ppm) 28.24, 28.72, 29.60, 40.48, 44.71, 56.14,62.02, 79.80, 109.22 (d, J=37.2 Hz), 139.25 (d, J=31.6 Hz), 146.06 (d,J=14.3 Hz), 155.2.4, 160.48, 164.25; IR (neat, NaCl) υ 2956, 2899, 1703,1593, 1403, 1359, 1251, 1151, 1092 cm⁻¹; Anal. Calcd. for C₁₆H₂₁O₂N₃F;C, 65.55; H, 7.51; N, 9.55; Found: C, 65.60, H, 7.24; N, 9.54.

2-exo-[5′-(2′-Fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (C1b)

To a stirred solution of 60 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-fluompyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.205 mmol) in 1 mL of CH₂Cl₂ at 0° C. under nitrogen was addeddropwise 1.0 mL of F₃CCO₂H. After 0.5 h, 25 mL of a saturated aqueousK₂CO₃ solution was added. The reaction mixture was extracted with two 50mL portions of CH₂Cl₂. The combined organic phase was dried over Na₂SO₄,filtered and concentrated under reduced pressure to give 43 mg of ayellow oil. This material was purified with column chromatography,eluting with 50% CMA80 in CH₂Cl₂ to give 30 mg of2-exo-[5′-(2′-fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (77%) as acolorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.55-1.65 (m, 5H), 1.90 (dd, J=8.9, 12.2), 2:78(dd, J=5.0, 9.0), 3.55 (m, 1H), 3.78 (m, 1H), 6.83 (dd, J=3.0, 8.5, 1H),7.87 (ddd, J=2.6, 8.3, 8.5, 1H), 8.07 (d, J=2.6, 1H); ¹³C NMR (CDCl₃) δ(ppm) 30.18, 31.38, 40.49, 44.40, 56.43, 62.83, 109.03 (d, J=36.7 Hz),140.04 (br d, J=7.7 Hz), 146.11 (d, J=14.0 Hz), 160.48, 164.25; IR(neat, NaCl) υ 3335, 2945, 1590, 1473, 1394, 1243, 910, 837, 639 cm⁻¹.

2-exo-[5′-(2′-Fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (C1b)

To 17 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-aminopyridinyl)]-7-azabicyclo[2,2,1]heptane(0.058 mmol) at room temperature under nitrogen was added 0.02 mL ofHF-Py (1.5 mmol, 70% HF in pyridine) with stirring. After 1 h, asolution of 26 mg of NaNO₂ in 0.2 mL of H₂O was added. After 0.5 h, thereaction mixture was warmed to 80° C. After 2 h, the reaction mixturewas slowly poured into 25 mL of a 50% aqueous NH₄OH solution. The waterphase was saturated with NaCl and extracted with three 25 mL portions ofEt₂O. The combined organic phase was dried over MgSO₄, filteted andconcentrated under reduced pressure to give 5.6 mg of a brown oil. Thismaterial was purified with column chromatography, eluting with 30% Et₃Nin Et₂O to give 4.5 mg of²-exo-[5′-(2′-fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (46%) as acolorless oil.

2-exo-[5′-(2′-Fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (C1b)

To a stirred solution of 30 mg of2-exo-[5′-(2′-Fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptane (0.157 mmol)in 0.5 mL of Et₂O at room temperature under nitrogen was added dropwise0.9 mL of a 1.0 M solution of HCl in Et₂O. After 0.5 h, the resultingwhite cloudy reaction mixture was concentrated under reduced pressure togive 37 mg of a white solid. This material was purified byrecrystallization in MeOH and Et₂O to give 18 mg of2-exo-[5′-(2′-fluoropyridinyl)]-7-azabicyclo[2,2,1]-heptanehydrochloride as a colorless crystal.

mp 177-179° C.; ¹H NMR (DMSO-d₆) δ (ppm) 1.61-1.95 (m, 4H), 2.22 (m,1H), 2.37 (m, 1H), 3.25 (m, 1H), 4.13 (m, 1H), 4.34 (m, 1H), 7.09 (dd,J=2.5, 8.5, 1H), 8.05 (ddd, J=2.6, 8.5, 8.5, 1H) 8.17 (d, J=2.6, 1H),8.95 (s, 1H), 9.57 (s, 1H); Anal. Calcd. for C₁₁H₁₆ClFN₂: C, 57.77; H,6.17; N, 12.25; Found: C, 57.62; H, 6.17; N, 12.26.

2-exo-[5′-(2′-Aminopyridinyl)]-7-azabicyclo[2,2,1]-heptane (C1d)Dihydrochloride

To a stirred solution of 230 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-aminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.079 mmol) in 0.5 mL of MeOH at room temperature under nitrogen wasadded dropwise 2 mL of 36% aqueous HCl solution. After 8 h, the reactionmixture was concentrated under reduced pressure to give 25 mg of ayellow oil. This material was purified by recrystallization in MeOH andEt₂O to give 18 mg of2-exo-[5′-(2′-aminopyridinyl)]-7-azabicyclo[2,2,1]-heptanedihydrochloride as a colorless crystal.

mp 270° C. decomposed; ¹H NMR (CD₃OD) δ (ppm) 1.85-2.12 (m, 5H), 2.39(dd J=5.0, 8.8, 1H), 3.36 (m, 1H), 4.34 (m, 1H), 4.48 (m, 1H), 7.05 (dd,J=8.5, 1H), 7.84 (s, 1H), 7.96 (d, J=8.5, 1H); Anal. Calcd. forC₁₁H₁₇Cl₂N₃: C, 50.39; H, 6.54; N, 16.03; Found: C, 50.12; H, 6.49; N,15.80.

7-tert-Butoxycarbonyl-2-exo-(3′-pyridinyl)-7-azabicyclo[2,2,1]-heptane

To a stirred mixture of 230 mg of7-tert-butoxycarbonyl-7-azabicyclo[2,2,1]-heptene (1.17 mmol), 481 mg of3-iodopyridine (2.34 mmol), 82 mg of n-Bu₄NCl (0.29 mmol), 198 mg ofKO₂CH (2.34 mmol) in 2.0 mL of DMF at room temperature under nitrogenwas added 26 mg of Pd(OAc)₂ (0.12 mmol). The reaction mixture was warmedto 80° C. After 24 h, the reaction mixture was warmed to 120° C. After 1h, the reaction mixture was diluted with 50 mL of 25% ethyl acetate inhexanes, filtered through an one inch pad of celite, concentrated underreduced pressure to give 500 mg of a yellow oil. This material waspurified by chromatatron, eluting with 25% followed by 50% ethyl acetatein hexanes to give 306 mg of7-tert-butoxycarbonyl-2-exo-(3′-pyridinyl)-7-azabicyclo[2,2,1]-heptane(94%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.43 (s, 9H), 1.45 (m, 1H), 1.57 (m, 1H),1.86-1.94, (m, 2H), 2.00 (dd, J=8.8, 12.4, 1H), 2.89 (dd. J=5.0, 8.8,1H), 4.22 (m, 1H), 4.38 (m, 1H), 7.21 (dd, J=3.7, 7.9, 1H), 7.65 (d,J=7.9, 1H), 8.44 (dd, J=1.9, 3.7, 1H), 8.48 (d, J=1.9, 1H); ¹³C NMR(CDCl₃) δ (ppm) 155.12, 148.94, 147.60, 140.97, 134.21, 123.45, 79.64,61.87, 55.74, 45.47, 39.64, 29.96, 28.59, 28.23.

Norchloroepibatidine Dihydrochloride (C1i)

To a stirred solution of 45 mg of7-tert-butoxycarbonyl-2-exo-(3′-pyridinyl)-7-azabicyclo[2,2,1]-heptane(0.162 mmol) in 2.5 mL of 5:1 Et₂O and MeOH at room temperature, undernitrogen was added dropwise 2 mL of 1M solution of HCl in ethyl ether(excess). After 8 h, the reaction mixture was concentrated under reducedpressure to give 50 mg of a white solid. This material was purified byrecrystallization in MeOH and Et₂O to give 35 mg of norchloroepibatidinedihydrochloride as a white solid.

mp: 239° C. (decomposed); ¹H NMR (CD₃OD) δ (ppm) 1.84-2.54 (m, 6H), 3.66(dd, J=5.0, 8.8, 1H), 4.43 (m, 1H), 4.68 (m, 1H), 7.39 (s, 1H), 8.04(dd, J,=3.7, 7.9, 1H), 8.66 (d, J=3.7, 1H), 8.69 (d, J=7.9, 1H), 9.08(s, 1H); Anal. Calcd. for C₁₁H₁₆C₁₂N₂−0.25H₂O: C,52.50; H, 6.48; N,10.98; Found: C, 52.45; H, 6.54; N, 10.94.

For the corresponding amine: ¹H NMR (CDCl₃) δ (ppm) 1.46-1.65 (m, 3H),1.68-1.75, (m, 2H), 1.92 (dd, J=8.8, 12.4, 1H), 2.82 (dd, J=5.0, 8.8,1H), 3.60 (m, 1H), 3.80 (m, 1H), 6.64 (dd, J=3.7, 7.9, 1H), 7.71 (d,J=7.9, 1H), 8.42 (dd, J=1.9, 3.7, 1H), 8.52 (d, J=1.92 1H), ¹³C NMR(CDCl₃) δ (ppm) 149.21, 147.36, 141.89, 134.40, 123.36, 62.7 3, 56.47,45.33, 40.18, 31.26, 30.03.

2-exo-[5′-(2′-Bromopyridinyl)]-7-azabicyclo[2,2,1]-heptane (C1c)

To 105 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-aminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.358 mmol) at 0° C. was added 0.41 mL of a 48% HBr solution in aceticacid (3.58 mmol) with stirring. After 0.5 h, 0.02 mL of Br₂ was addeddropwise followed by a solution of NaNO₂ in 0.5 mL of water. After 0.5h, the resulting tarry reaction mixture was diluted with 25 mL of 1:1NH₄OH and H₂O then extracted with three 25 mL portions of 10% MeOH inCHCl₃. The combined organic phase was washed with a saturated aqueousNa₂SO₃ solution, dried over MgSO₄, filtered and concentrated underreduced pressure to give 120 mg of a brown oil. This material waspurified by column chromatography, eluting with 20% triethylamine inether to give 35 mg of a colorless oil, which was purified again withcolumn chromatography, eluting with a. solution of 96:3.1CHCl₃:MeOH:NH₄OH to give 31 mg of2-exo-[5′-(2′-bromopyridinyl)]7-azabicyclo[2,2,1]-heptane (36%) as acolorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.55-1.73 (m, 3H), 1.82 (m, 2H), 1.93 (dd, J=8.8,12.4, 1H), 2.78 (dd, J=5.0, 8.8, 1H), 3.64 (m, 1H), 4.88 (m, 1H), 7.40(d, J=8.2, 1H), 7.71 (dd, J=2.4, 8.2, 1H), 8.27 (d, J=2.4, 1H); ¹³C NMR(CDCl₃) δ (ppm) 149.45, 140.15, 139.16, 137.53, 127.90, 62.77, 56.87,44.24, 39.53, 30.76, 29.09.

Reference: Org. Synth. III, 136, 1955.

2-exo-[5′-(2′-Bromopyridinyl)]-7-azabicyclo[2,2,1]-heptane(C1c)Dihydrochloride

To a stirred Solution of 31 mg of2-exo-[5′-(2′-bromopyridinyl)]-7azabicyclo[2,2,1]-heptane (0.114 mmol)in 0.5 mL of 2:1 Et₂O and MeOH at room temperature was added dropwise1.0 mL of a 1.0 M HCl solution in Et₂O (1 mmol). After 2 h, the solventswere removed under reduced pressure and the resulting white solid wasredissolved into MeOH, filtered and recrystallized from MeOH and Et₂O togive 31 mg of 2-exo-[5′-(2′-bromopyridinyl)]-7-azabicyclo[2,2,1]-heptanedihydrochloride as a white solid.

mp 183-185° C.; Anal. Calcd. for C₁₁H₁₃BrN₂-2HCl: C, 40.52; H, 4.64; N,8.59; Found: C, 40.49; H, 4.63; N, 18.54.

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-hydroxypyridinyl)]-7-azabicyclo[2.2.1]-heptane(C1l)

To a stirred solution of 52 mg of7-tert-butoxycarbonyl-2-exo-[3′-(6′-aminopyridinyl))-7-azabicyclo[2,2,1]-heptane(0.18 mmol) in 1 mL of AcOH at 0° C. was added 62 mg of NaNO₂ (0.86mmol) in 1.0 mL of water. After 2 h, 8 mL of saturated aqueous solutionof Na₂CO₃ was added (until pH≧10) and the reaction mixture was warmed toroom temperature. After 1 h, the reaction mixture was poured into 25 mLof 1:1 NH₄OH and H₂O, extracted with three 25 mL portions of CHCl₃. Thecombined organic phase was dried over MgSO₄, filtered and concentratedunder reduced pressure to give 40 mg of clean7-tert-butoxycarbonyl-2-exo-[5′-(2′-hydroxypyridinyl)]-7-azabicyclo[2,2,1]heptaneas a colorless oil. This material was used without further purification.

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicyclo[2,2,1]-heptane(C12)

To a stirred solution of 40 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-hydroxypyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.34 mmol) in 4.0 mL of pyridine at room temperature was added 0.5 mLof Tf₂O (3.4. mmol). After 8 h, the reaction mixture was poured into 25mL of 1:1 NH₄OH and H₂O, extracted with three 25 mL portions of CHCl₃.The combined organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure to give 60 mg of a yellow oil. Thismaterial was filtered through a one inch pad of silicon gel, elutingwith 25% ethyl acetate in hexanes to give 53 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptane(88%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.44 (s, 9H), 1.52-1.69, (m, 2B), 1.79-1.86 (m,3H), 2.03 (dd, J=9.7, 13.4, 1H), 3.93 (dd, J=5.3, 9.8, 1H), 4.20 (m,1H), 4.38 (m, 1H), 7.11 (d, J=9.1, 1H), 7.88 (dd, J=2.6, 9.1, 1H), 8.25(d, J=2.7, 1H); ¹³C NMR (CDCl₃) δ (ppm) 155.69, 154.78, 147.78, 142.74,139.76, 118.57 (q, J=320), 115.37, 80.48, 61.88, 56.16, 44.79, 40.40,30.01, 29.60, 28.73, 28.63.

2-exo-[5′-(2′-Trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptane(C1g)

To a stirred solution of 53 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptane(0.12 mmol) in 0.5 mL of CH₂Cl₂ at room temperature was added 0.5 mL ofTFA. After 1 h, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in 50 mL of CHCl₃ and washed with 50mL of 1:1 of NH₄OH and H₂O. The aqueous phase was extracted with two 25mL portions of CHCl₃. The combined organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure to give 39 mg of2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptaneas a yellow oil (100%). This material was convened into HCl salt withoutfurther purification.

¹H NMR (CDCl₃) δ (ppm) 1.11-1.18, (m, 2H), 1.41-1.59 (m, 3H), 1.85 (dd,J=9.7, 13.4, 1H), 2.73 (dd, J=5.3, 9.8, 1H), 3.51 (m, 1H), 3.74 (m, 1H),7.01 (d, J=9.1, 1H), 7.97 (dd, J=2.6, 9.1, 1H), 8.21 (d, J=2.7, 1H); ¹³C NMR (CDCl₃) δ (ppm) 154.19, 147.46, 143.58, 139.86, 118.67 (q, J=320),114.72, 62.69, 56.35, 44.42, 40.54, 31.47, 30.35.

2-exo-[5′-(2′-Trifluoromethanesulfonyloxypyridinyl)]-7-azabicyclo[2,2,1]-heptane(C1g) Hydrochloride

To a stirred solution of 39 mg2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptane(0.13 mmol) in 0.5 mL of Et₂O and 0.0015 mL of MeOH at room temperatureunder N₂ was added 1.0 mL of 1.0 M solution of HCl (1.0 mmol) in Et₂O.After 2 h, the stirrer was stopped and the solvents were removed with apipet. The resulting white solid was washed with two 0.5 mL portions ofEt₂O and dried under vacuum to give 39 mg of2-exo-[5′-(2′-trifluoromethanesulfonyloxypyridinyl)]-7-azabicycl[2,2,1]-heptanehydrochloride as a white solid (90%).

mp: 204-205° C.; Anal. Calcd. for C₁₂H₁₄ClF₃N₂SO₃: C, 40.29; H, 3.94; N,7.83; Found: C, 40.36; H, 4.01; N, 7.72.

2-exo-[5′-(2′-N,N-Dimethylaminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(C1h)

To a stirred solution of 102 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-aminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.348 mmol) in MeCN at room temperature under N₂ was added 1.5 mL of a37% polyformaldehyde solution in H₂O (20 mmol) followed by 450 mg ofNaBH₃CN (6.8 mmol) as a solid. After 2 h, 0.5 mL of HOAc was addeddropwise. After 0.5 h, the reaction mixture was poured into 50 mL of a10% aqueous NaOH solution and extracted with three 50 mL portions ofCHCl₃. The combined organic phase was washed with a saturated aqueousNaCl solution, dried over anhydrous Na₂SO₄, filtered and concentratedunder reduced pressure to give 130 mg of a white solid. This materialwas purified by column chromatography, eluting with 50% ethyl acetate inhexanes to give 97 mg of2-exo-[5′-(2′-N,N-Dimethylaminopyridinyl)]-7-azabicyclo[2,2,1]-heptaneas a white solid.

mp 99.5-100° C.; ¹H NMR (CDCl₃) δ (ppm) 1.43 (s, 9H), 1.49-1.60 (m, 2H),1.77-1.87 (m, 3H), 1.94, (m, 1H), 2.74 (m, 1H), 3.05 (s, 6H), 4.09 (m,1H), 4.34 (m, 1H), 6.48 (d, J=8.8, 1H), 7.45 (dd, J=2.4, 8.8, 1H), 8.00(d, J=2.4, 1H); ¹³C NMR (CDCl₃) δ (ppm) 158.36, 155.42, 146.45, 135.80,128.66, 105.96, 79.42, 67.99, 58.35, 48.20, 41.40, 38.28, 30.71, 28.34.

Reference: J. Med. Chem. 38, 2978, 1995.

2-exo-[5′-(2′-N,N-Dimethylaminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(C1h) Dihydrochloride

To a stirred solution of 66 mg of7-tert-butoxycarbonyl-2-exo-[5′-(2′-dimethylaminopyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.21 mmol) in 0.5 mL of CH₂Cl₂ at room temperature was added 0.5 mL ofTFA. After 1 h, the reaction mixture was concentrated under reducedpressure. The residue was dissolved in 50 mL of CHCl₃ and washed with 50mL of 1:1 of NH₄OH and H₂O. The aqueous phase was extracted with two 25mL portions of CHCl₃. The combined organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure to give 37 mg of2-exo-[5′-(2′-dimethylaminopyridinyl)]-7-azabicyclo[2-2,1]-heptane as ayellow oil (95%). This material was converted into HCl salt withoutfurther purification and recrystallized from MeOH and Et₂O to give 15 mgof2-exo-[5′-(2′-N,N-dimethylaminopyridinyl)]-7-azabicyclo[2,2,1]-heptanedihydrochloride monohydrate as a light yellow solid.

mp: 222° C. dec.; ¹H NMR (CDCl₃) δ (ppm) 1.46-1.57, (m, 3H), 1.72-1.84(m, 3H), 2.63 (dd, J=5.5, 9.6, 1H), 2.95 (s, 6H), 3.39 (m, 1H), 3.63 (m,1H), 6.38 (d, J=9.5, 1H), 7.36 (dd, J=2.7, 9.5, 1H), 7.92 (d, J=2.7,1H); ¹³C NMR (CDCl₃) δ (ppm) 158.14, 146.20 136.11, 128.98, 105.80,62.96, 56.37, 44.67, 39.81, 38.20, 30.67, 29.71; Anal. Calcd. forC₁₃H₂₃Cl₂N₃O: C, 50.65; H, 7.52; N, 13.63; Found: C, 50.86; H, 7.35; N,13.38.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C14)

To a resealable reaction vessel containing degassed DMF (10 mL) wasadded 7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (1.04 g, 5.12mmol), 2-chloro-3-amino-5-iodopyridine (2.4 g, 10.2 mmol), Pd(OAC)₂ (67mg, 0.30 mmol), n-butyl ammonium chloride (370 mg, 1.33 mmol), andpotassium formate (862 mg, 10.2 mmol). The reaction tube was sealedunder nitrogen, placed into an 105° C. oil bath, and let stir for 24 h.The reaction was then diluted with ethyl acetate, filtered through acelite pad, then the organics were extracted with 1:1 NH₄OH:H₂O (150mL). The combined organic extracts were dried with sodium sulfate,concentrated, then the residue was purified by flash chromatographyusing 1:1 hexane, ethyl acetate to yield7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(319 mg, 19%) as a colorless solid.

¹H NMR (CDCl₃) δ (ppm) 1.43 (s, 9H), 1.44-1.61 (m, 2H), 1.70-1.85 (m,3H), 1.95 (dd, J=9.0, 12.3 Hz, 1H), 2.77 (dd, J=5.1, 9.0 Hz, 1H), 4.15(br s, 3H), 4.34 (br s, 1H), 7.05 (s, 1H, pyridyl CH), 7.65 (s, 1H,pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.15 (3C), 28.59, 29.58, 40.6,44.63, 55.97, 61.80, 79.62, 120.71, 134.77, 137.38, 139.30, 141.33,155.18.

7-tert-Butoxycarbonyl-2-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C14)

To a resealable reaction vessel containing DMF (9 mL) was added7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (1.31 g, 6.71mmol), 2-chloro-3-amino-5-iodopyridine (3.17 g, 8.41 mmol), Pd(OAC)₂(121 mg, 0.54 mmol), n-butyl ammonium chloride (470 mg, 1.69 mmol), andpotassium formate (1.1 g, 13.1 mmol). The reaction tube was sealed undernitrogen, placed into an 100° C. oil bath, and let stir for 24 h. Thereaction was then diluted with ethyl acetate, filtered through a celitepad, then the organics were extracted with 1:1 NH₄OH:H₂O (150 mL). Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography using 1:1hexane:ethyl acetate to yield7-tert-Butoxycarbonyl-2-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(1.00 g, 46%) as a 3:1 endo:exo mixture.

¹H NMR (CDCl₃) δ (ppm) [exo]1.43 (s, 9H), 1.44-1.61 (m, 2H), 1.70-1.85(m, 3H). 1.95 (dd, J=9.0, 12.3 Hz, 1H), 2.77 (dd, J=5.1, 9.0 Hz, 1H),4.15 (br s, 3H), 4.34 (br s, 1H), 7.05 (s, 1H, pyridyl CH), 7.65 (s, 1H,pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.15 (3C), 28.59, 29.58, 40.6,44.63, 55.97, 61.80, 79.62, 120.71, 134.77, 137.38, 139.30, 141.33,155.18.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C15)

To a resealable reaction vessel containing degassed DMF (5 mL) was added7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (0.500 g, 2.56mmol), 2-fluoro-3-amino-5-iodopyridine (788 mg, 3.36 mmol), Pd(OAc)₂ (50mg, 0.22 mmol), n-butyl ammonium chloride (116 mg, 0.417 mmol), andpotassium formate (288 mg, 3.42 mmol). The reaction tube was sealedunder nitrogen, placed into an 105° C. oil bath, and let stir for 2 h.The reaction was then diluted with ethyl acetate, filtered through acelite pad, then the organics were extracted with 1:1 NH₄OH:H₂O (150mL). The combined organic extracts were dried with sodium sulfate,concentrated, then the residue was purified by flash chromatographyusing 2:1 hexane:ethyl acetate to yield7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(366 mg, 46%) as a colorless solid.

mp 80-82° C.; ¹H NMR (CDCl₃) 8 (ppm) 1.44 (s, 9H), 1.44-1.60 (m, 2H),1.70-1.88 (m, 3H), 1.95 (dd, J=9.0, 12.3 Hz, 1H), 2.78 (dd, J=5.2, 8.9Hz, 1H), 3.86 (br s, 2H), 4.13 (br s, 1H), 4.34 (br s, 1H), 7.11 (d, 1H,J_(HF)=10.5 Hz, pyridyl CH), 7.37 (s, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ(ppm) 28.19 (3C), 28.63, 29.59, 40.3, 44.67, 55.9, 61.97, 79.63, 122.78(J_(CF)=5.2 Hz), 129.34 (J_(CF)=28.6 Hz), 133.23 (J_(CF)=13.1 Hz),139.73 (J_(CF)=4.1 Hz), 149.72, 154.32 (J_(CF)=118 Hz). AnalyticalCalculated for C₁₆H₂₂N₃O₂F: C, 62.52; H, 7.21; N, 13.67; Found: C,62.53; H, 7.29; N, 13.54.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(C16)

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Chloro-3′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(218 mg, 0.673 mmol), 10% Pd/C (230 mg), and methanol (4 mL) were placedinto a Fisher-Porter tube under nitrogen. The flask was evacuated,refilled with hydrogen gas @ 40 psi, then the reaction was allowed toshake for 7 h. Solvent removal was followed by flash chromatographyusing CHCl₃:CH₃OH:NH₄OH (45:9:1) to give7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(156 mg, 79%) as a colorless solid.

mp 183-184° C.; ¹H NMR (CDCl₃) δ (ppm) 1.43 (s, 9H), 1.5-1.65 (m, 2H),1.7-2.0 (m, 4H), 2.79 (dd, J=5.2, 8.6Hz, 1H), 3.75 (br s, 2H), 4.13 (brs, 1H), 4.35 (br s, 1H), 6.96 (s, 1H, pyridyl CH), 7.88 (s, 1H, pyridylCH), 7.92 (dd, J=2.6 Hz, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.24(3C), 28.7, 29.7, 39.8, 45.1, 55.8, 61.6, 79.58, 119.62, 135.50, 139.27,141.27, 142.47, 155.23.

2-exo-[5′-(3′-Chloro-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C18)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(100 mg, 0.325 mmol) in concentrated hydrochloric acid (4 mL) was addedsodium nitrite (570 mg, 8.3 mmol). Copper (1) chloride (570 mg, 5.8mmol) was then added in small portions and stirring continued for 30 min0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O (50mL) and extracted with ethyl acetate. The combined organic layers weredried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive2-exo-[5′-(3′-Chloro-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(31 mg, 42%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.5-1.8 (m, 5H), 1.90 (dd, J=9.1, 12.1 Hz, 1H),2.74 (dd, J=4.7, 8.5 Hz, 1H), 3.55 (br s, 1H), 3.78 (br s, 1H), 7.95-8.2(m, 2H); ¹³C NMR (CDCl₃) δ (ppm) 30.32, 31.41, 40.55, 44.03, 56.24,62.72, 116.6 (J_(CF)=35.4 Hz), 4 other carbons with complicatedsplitting patterns.

2-exo-[5′-(3′-Chloro-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C18) Hydrochloride

2-exo-[5′-(3′-Chloro-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(31 mg, 0.137 mmol) was dissolved in ether (2 mL) and then 1M HCl inether (1 mL) was added dropwise. The reaction was allowed to stir for 30min at room temperature. The solvent was removed under reduced pressureand the remaining2-exo-[5′-(3′-Chloro-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 0.5 Hydrate was pumped overnight to give (34 mg, 91%) as acolorless solid.

mp 176-180° C.; Analytical Calculated for C₁₁H₁₃N₂FCl₂×0.5 H₂O; C,48.55; H, 5.19; N, 10.29; Found: C, 48.85; H, 4.99; N, 10.24.

Experimental Procedures for Scherme C4 Shown in FIG. 47-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(C20)

To a stirred solution of2-exo-[5′-(2′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (968 mg, 3.30mmol) in methylene chloride (8 mL) and acetic acid (7 mL) under nitrogenat 0° C. was added bromine (0.260 mL, 5.05 mmol) followed bytriethylamine (0.260 mL). After stirring the reaction for 16 h, themixture was poured into a 1:1 NH₄OH:H₂O (100 mL) solution and extracted3× with chloroform. The combined organic extracts were dried withmagnesium sulfate, concentrated, then the residue was purified by flashchromatography using 4:1 ether triethylamine to give7-tert-butoxycarbony-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2-2.1]-heptane(1.044 g, 85%) as a colorless solid.

mp 129-130° C.; ¹H NMR (CDCl₃) δ (ppm) 1.44 (s, 9H), 1.40-1.55 (m, 2H),1.70-1.84 (m, 3H), 1.90 (dd, J=9.0, 12.3 Hz, 1H), 2.70 (dd, J=4.8, 8.8Hz, 1H), 4.08 (br s, 1H), 4.33 (br s, 1H), 7.62 (s, 1H, pyridyl CH),7.83 (s, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.3 (3C), 28.7, 29.7,40.3, 44.6, 55.7, 62.0, 79.7, 104.6, 132.9, 138.8, 145.5,154.0, 154.9;Analytical Calculated for C₁₆H₂₂O₂N₃Br: C, 52.18; H, 6.02; N, 11.41;Found: C, 52.23; H, 6.11; N, 11.35.

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-amino-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptane(C21)

To a resealable reaction tube under nitrogen was added7-tert-Butoxycarbonyl-2-exo-[5′-(2′-amino-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(403 mg, 1.08 mmol), Pd(OAC)₂ (25 mg, 0.011 mmol), P(o-tolyl)₃ (60 mg,0.02 mmol), sodium carbonate (230 mg, 2.17 mmol), phenylboronic- acid(210 mg, 1.72 mmol), degassed water (0.800 mL) and DME (4 mL). Thereaction was heated at 80° C. for 1.5 h. The mixture was poured intosaturated sodium bicarbonate and extracted with ethyl acetate 3×. Theorganic layers were dried with sodium sulfate, concentrated, then theresidue was purified by flash chromatography using 1:2 hexane:ethylacetate as eluent to provide7-tert-Butoxycarbonyl-2-exo-[5′-(2′-amino-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptane (347 mg, 88%) as acolorless solid.

¹H NMR (CDCl₃) δ (ppm) 1.38 (br s, 9H), 1.38-1.65 (m, 2H), 1.75-2.0 (m,4H), 2.78 (dd, J=5.2, 8.6 Hz, 1H), 4.16 (s, 1H), 4.35 (s, 1H), 4.60 (brs, 2 NH), 7.3-7.45 (m, 6H), 7.92 (d, J=2.2 Hz, 1H); ¹³C NMR (CDCl₃) δ(ppm) 28.2, 28.8, 29.7, 40.2, 44.8, 55.5, 62.1, 79.3, 121.6, 127.5,128.6(2C), 128.8(2), 131.7, 136.5, 138.2, 145.6, 154.3, 154.8.Analytical Calculated for C₂₂H₂₇N₃O₂: C, 72.30; H, 7.45; N, 11.50;Found: C, 71.74; H, 7.45; N, 11.26.

2-exo-[5′-(2′,3′-Bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane (C22)

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Amino-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(230 mg, 0.622 mmol) was dissolved in concentrated HBr (3 mL) followedby sodium nitrite (800 mg, 11.6 mmol) and CuBr (2 g, 13.9 mmol)addition. The reaction was allowed to stir overnight at roomtemperature. The reaction contents were poured into a 3:1 mixture ofwater:NH₄OH, extracted with chloroform, dried with sodium sulfate andconcentrated. The residue was purified by flash chromatography using amixture of chloroform, methanol, and NH₄OH (950:20:1) to provide2-exo-[5′-(2′,3′-Bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane (52 mg,25%) as a colorless oil.

mp oil ° C; ¹H NMR (CDCl₃) δ (ppm) 1.4-1.7 (m, 5H), 1.87 (dd, J=9.0,12.1 Hz, 1H), 2.70 (dd,J=4.9, 9.0 Hz, 1H), 3.56 (s, 1H), 3.80 (s, 1H),8.1 0 (d, J=2.1 Hz, 1H), 8.21 (d, J=2.1 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm)30.32, 31.43, 40.39, 44.05, 56.24, 62.64, 123.34, 140.55, 140.66,143.40, 147.30.

2-exo-[5′-(2′,3′-Dibromopyridinyl)]-7-azabicyclo[2.2.1]-heptane (C22)Hydrochloride

2-exo-[5′-(2′,3′-Bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane (43 mg,0.130 mmol) was dissolved in methylene chloride (0.800 mL). A 1M HCl inether solution (1 mL) was then added dropwise. The solvents were removedunder reduced pressure to provide2-exo-[5′-(2′,3′-Bromopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride (51 mg, Quantitative) as a colorless solid.

mp 244-246° C.; Analytical Calculated for C₁₁H₁₃N₂Br₂Cl: C, 35.85; H,3.56; N, 7.60; Found: C, 35.67; H, 3.62; N, 7.45.

2-exo-[5′-(3′-phenyl}-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C23a)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-aminopyridinyl)]-7-azabicyclo[2-2.1]-heptane(150 mg, 0.410 mmol) in concentrated hydrofluoric acid/pyridine (0.6 mL)was prepared in a plastic vessel. Sodium nitrite (110 mg, 1.6 mmol) wasthen added and stirring continued for 45 minutes at room temperature.The reaction was then heated to 100° C. for one hour. The mixture wasthen poured into a solution of 1:1 NH₄OH:H₂O (50 mL) and extracted withethyl acetate. The combined organic layers were dried with magnesiumsulfate, concentrated, then the residue was purified via flashchromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) to give2-exo-[5′-(3′-phenyl-2′-fluoropyridinyl)]azabicyclo[2.2.1]-heptane (91mg, 83%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.76 (m, 4H), 1.93 (dd, J=9.3, 12.3 Hz, 2H),2.04 (s, 1H), 2.83 (dd, J=6.0, 9.3 Hz, 1H), 3.62 (br s, 1H), 3.80 (br s,1H), 7.33-7.60 (m, 5H), 7.98 (dd, J_(F)=2.4, 9.6 Hz, 1H), 8.07 (t,J_(F)=1.5 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 29.97, 31.23, 40.32, 44.35,56.36, 62.74, 123.01(d, J_(CF)=28.5 Hz), 128.5 (m, 4C), 134.15 (d,J_(CF)=5.1 Hz), 139.70 (d, J_(CF)=4.2 Hz), 140.34 (d, J_(CF)=18.9 Hz),144.59 (d, J_(CF)=57 Hz), 157.39, 160.55.

2-exo-[5′-(3′-phenyl}-2′-fluoropyridinyl)]-7-azabicyclo [2.2.1]-heptane(C23a) Hydrochloride

2-exo-[5′-(3′-phenyl-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(91 mg, 0.339 mmol) was dissolved in methylene chloride (2.5 mL) andthen 1M HCl in ether (1.6 mL) was added dropwise. The reaction wasallowed to stir for 30 min at room temperature. The solvent was removedunder reduced pressure and the remaining2-exo-[5′-(3′-phenyl}-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 1.25 Hydrate was pumped overnight to give (90 mg, 81%) asa colorless solid.

Analytical Calculated for C₁₇H₁₉N₂CIF×1.25 H₂O: C, 62.38; H, 6.62; N,8.56; Found: C, 62.40; H, 6.01; N, 8.56.

2-exo-[5′-(3′-Phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(C24)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(165 mg, 0.451 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 1 h. Thereaction was then decanted into a saturated NaHCO₃ solution andextracted with chloroform 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-Phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(116 mg, 97%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.38-1.82 (m, 4H), 1.87 (dd,J=9.0, 12.2 Hz, 1H),2.75 (dd, J=5.1, 8.7 Hz, 1H), 3.54 (br s, 1H), 3.73 (br s, 1H), 4.61 (brs, 2H), 7.30-7.47 (m, 6H), 7.93 (s, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ(ppm) 29.71, 30.82, 39.91, 44.68, 56.28, 62.85, 121.55, 127.48,128.61(2C), 128.82(2C), 132.28, 136.85, 138.23, 145.51, 154.15.

2-exo-[5′-(3′-Phenyl-2′- aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(C24) Hydrochloride

2-exo-[5′-(3′-Phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (96mg, 0.362 mmol) was dissolved in methylene chloride (1.5 mL) and then 1MHCl in ether (3 mL) was added dropwise. The reaction was allowed to stirfor 1 h. at room temperature. The solvent was removed under reducedpressure and the remaining2-exo-[5′-(3′-Phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane 2.5Hydrochloride 1.25 Hydrate was pumped overnight to give (127 mg, 92%) asa colorless solid.

mp Decomposed >200° C.: Analytical Calculated forC₁₇H₂₄N₃O_(1.25)Cl_(2.5); C, 53.87; H, 6.38: N, 11.09; Found: C, 53.95:H, 6.33-1 N, 10.68.

2-exo-[5′-(3′-phenyl-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C23)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(217 mg, 0.594 mmol) in concentrated hydrochloric acid (1.5 mL) wasadded sodium nitrite (800 mg, 11.6 mmol). Copper (1) chloride (800 mg,8.1 mmol) was then added in small portions and stirring continued for 30min 0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O(50 mL) and extracted with ethyl acetate. The combined organic layerswere dried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive2-exo-[5′-(3′-Phenyl-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(100 mg, 59%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.78 (m, 5H), 1.93 (dd, J=9.0, 12.1 Hz, 1H),2.81 (dd, J=4.9, 8.9 Hz, 1H), 3.61 (br s, 1H), 3.78 (br s, 1H),7.36-7.48 (m, 5H), 7.76 (s, pyridyl 1 CH), 8.29 (s, pyridyl 1 CH); ¹³CNMR (CDCl₃) δ (ppm) 30.07, 31.30, 40.27, 44.45, 56.28, 62.64, 127.98,128.11(2C), 129.23(2C), 136.19, 137.69, 138-54, 141.41, 146.92, 147.33.

2-exo-[5′-(3′-phenyl-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(C23) Monohydrochloride

2-exo-[5′-(3′-Phenyl-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(70 mg, 0.246 mmol) was dissolved in ether (1.5 mL) and then 1M HCl inether (1.5 mL) was added dropwise. The reaction was allowed to stir for30 min at room temperature. The solvent was removed under reducedpressure and the remaining2-exo-[5′-(3′-Phenyl-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 0.75 Hydrate was pumped overnight to give (80 mg, 97%) asa colorless solid.

mp 144-147° C.; Analytical Calculated for C₁₇H_(19.5)N₂O_(0.75)Cl₂: C,60.99; H, 5.87; N, 8.37; Found: C, 60.67; H, 5.80; N, 8.18.

Experimental Procedures for Scheme D1 Shown in FIG. 62-exo-[5′-(3′-Fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2b)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-aminopyridinyl)]-7-5-25azabicyclo[2.2.1]-heptane(81 mg, 0.280 mmol) in 70% HF-pyridine (1.5 mL) inside a plasticreaction vessel at 0° C. was added sodium nitrite (150 mg, 2.2 mmol).Stirring continued for 30 min before being heated at 100° C. for anadditional 30 min. The reaction was then poured into a solution of 1:1NH₄OH:H₂O (50 mL) and extracted with ethyl acetate. The combined organiclayers were dried with magnesium sulfate, concentrated, then the residuewas purified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1)to give 2-exo-[5′-(3′-Fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (36mg, 67%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.75 (m, 4H), 1.86-1.98 (m, 2H), 2.82 (dd,J=4.9, 8.8 Hz, 1H), 3.60 (br s, 1H), 3.81 (br s, 1H), 7.58 (dt, J=2.3,10.1 Hz, 1 pyridyl CH), 8.28 (d, J=2.7 Hz, 1 pyridyl CH), 8.33 (s, 1pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm)30.06, 31.26, 40.26, 44.56, 56.29,62.64, 121.33 (J_(CF)=18.2 Hz), 135.49 (J_(CF)=23.4 Hz), 144.48(J_(CF)=3.3, 49.9 Hz), 157.61, 161.68.

2-exo-[5′-(3′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2c)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(68 mg, 0.232 mmol) in concentrated hydrochloric acid (2 mL) was addedsodium nitrite (400 mg, 5.8 mmol). Copper (1) chloride (400 mg, 4.0mmol) was then added in small portions and stirring continued for 30 minat 0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O(50 mL) and extracted with ethyl acetate. The combined organic layerswere dried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive 2-exo-[5′-(3′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (35 mg,72%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.8 (m, 5H), 1.90 (dd, J=8.8, 11.9 Hz, 1H),2.77 (dd, J=4.9, 8.8 Hz, 1H), 3.59 (br s, 1H), 3.79 (br s, 1H), 7.82 (t,J=2.1 Hz, 1 pyridyl CH), 8.39 (br s, 2 pyridyl CH); ¹³C NMR (CDCl₃) δ(ppm) 30.15, 31.33, 40.26, 44.72, 56.26, 62.58, 131.83, 134.37, 143.55,146.14, 146.90.

2-exo-[5′-(3′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2c)Hydrochloride

2-exo-[5′-(3′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (35 mg,0.168 mmol) was dissolved in ether (2 mL) and then 1M HCl in ether (1mL) was added dropwise. The reaction was allowed to stir for 30 min atroom temperature. The solvent was removed under reduced pressure and theremaining 2-exo-[5′-(3′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 0.25 Hydrate was pumped overnight to give (38 mg, 90%) asa colorless solid.

mp 219-221° C.; Analytical Calculated for C₁₁H₁₄N₂Cl₂×0.25 H₂O; C,52.92; H, 5.85; N, 11.22; Found: C, 53.19; H, 5.71; N, 11.17.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D1.1)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(111 mg, 0.379 mmol) in methylene iodide (3.0 mL) and isoamyl nitrite(1.0 mL) was allowed to stir at room temperature for 30 min. H1 (0.011mL) was then added. After 24 h the reaction was decanted into 1:1NH₄OH:H₂O and then extracted with chloroform 3×. The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 9:1 hexane:ethyl acetate aseluent to give 2-exo-[5′-(3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(81 mg, 53%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45 (s, 9H), 1.50-1.67 (m, 2H), 1.75-1.92 (m,3H), 1.99 (dd, J=8.9, 12.4 Hz, 1H), 2.82 (dd, J=4.9, 8.9 Hz, 1H), 4.20(br s, 1H), 4,39 (br s, 1H), 7.99 (t, J=1.9 Hz, 1H, pyridyl CH), 8.42(d, J=1.9 Hz, 1H), 8.66 (d, J=1.9 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 28.27(3C), 28.70, 29.72, 40.11, 45.27, 55.8, 61.60, 79.89, 93.67, 142.48,143.10, 147.41, 153.58, 154.7.

2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2e)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(81 mg, 0.202 mmol) in methylene chloride (2.0 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (2.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa saturated NaHCO₃ solution and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (45 mg, 74%)as a colorless oil.

¹M NMR (CDCl₃) δ (ppm) 1.5-1.85 (m, 5H), 1.94 (dd, J=9.0, 12.5 Hz, 1H),3H), 2.77 (dd, J=5.1, 9.0Hz, 1H), 3.68 (br s, 1H), 3.88 (br s, 1H), 8.17(t, J=1.9 Hz, 1H, pyridyl CH), 8.46 (d, J=1.9 Hz, 1 pyridyl CH), 8.64(d, J=1.9 Hz, 1 pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 29.46, 30.97,39.75, 44.68, 56.58, 62.60, 93.75, 142.88, 143.38, 147.59, 153.42.

2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2e)Hydrochloride

2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (45 mg, 0.150mmol) was dissolved in 1:1 ether:methylene chloride (2 mL) and then 1MHCl in ether (1.5 mL) was added dropwise. The reaction was allowed tostir for 30 min at room temperature. The solvent was removed underreduced pressure and the remaining2-exo-[5′-(3′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane 1.75Hydrochloride Hydrate was pumped overnight to give (56 mg, 98%) as acolorless solid.

mp 223-225° C.; Analytical Calculated for C₁₁H_(16.67),N₂lOCl_(1.75); C,34.59; H, 4.42; N, 7.33; Found: C, 34.56; H, 4.24; N, 6.97.

2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2a)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(64 mg, 0.218 mmol) in methylene chloride (2.0 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (1.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa solution of 1:1 NH₂OH:H₂O and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (28 mg, 68%)as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.8 (m, 5H), 1.89 (dd, J=9.3, 12.6 Hz, 1H),3H), 2.74 (dd, J=5.1, 8.8 Hz, 1H), 3.30 (br s, 2H), 3.60 (br s, 1H),3.78 (br s, 1H), 7.06 (s, 1 pyridyl CH), 7.89 (dd, J=2.5, 6.7 Hz, 2pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 29.59, 30.97, 39.86, 44.87, 56.38,62.57, 119.89, 135.14, 139.24, 141.88, 142.48.

2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T2a)Dihydrochloride

2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (28 mg, 0.148mmol) was dissolved in 1:1 ether:methylene chloride (2 mL) and then 1MHCl in ether (1.5 mL) was added dropwise. The reaction was allowed tostir for 30 min at room temperature. The solvent was removed underreduced pressure and the remaining2-exo-[5′-(3′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptaneDihydrochloride 0.25 Hydrate 0.75 Methanol was pumped overnight to give(30 mg, 70%) as a colorless solid.

mp 255-256° C.; Analytical Calculated for C_(11.75)H_(20.5)N₃Cl₂O; C,48.54; H, 7.10; N, 14.45; Found: C, 48.51; H, 6.81; N, 14.11.

Experimental Procedures for Scheme D3 Shown in FIG. 82-exo-[5′-(3′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3a)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(112 mg, 0.303 mmol) in methylene chloride (1.4 mL) and trifluoroaceticacid (1.4 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated K₂CO₃ solution and extractedwith methylene chloride 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using (CHCl₃:CH₃OH:NH₄OH/45:9:1) as eluent to give2-exo-[5′-(3′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (77mg, 95%) as a colorless oil.

¹H NMR (CD₃OD) δ (ppm) 1.42-1.48 (m, 1H), 1.54 (t, J=8.3 Hz, 1H),1.58-1.68 (m, 3H), 1.91 (dd, J=9.0, 12.2 Hz, 1H), 3.50 (br s, 1H), 3.70(br s, 1H), 4.87 (br s, 2H), 7.77 (s, 1H, pyridyl CH), 7.81 (s, 1H,pyridyl CH); ¹³C NMR (CD₃OD) δ (ppm) 29.8, 31.5, 40.9, 45.5, 57.7, 63.8,105.5, 133.6, 141.0, 146.0, 155.9.

2-exo-[5′-(3 ′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptanesalt (T3a) Hydrochloride

To a stirred solution of2-exo-[5′-(3′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2-2.1]-heptane (37mg, 0.138 mmol) in methylene chloride (0.500 mL) was added 1.0 M HClsolution in ether (1.3 mL) dropwise. The reaction was allowed to stirfor 30 min. The solvent was then removed under reduced pressure and theresidue recrystallized to provide the salt of2-exo-[5′-(3′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (26mg, 52%) as a colorless crystal.

mp 237-240° C.; Analytical Calculated for C₁₁H_(1.65)N₃BrCl_(2.5): C,36.77; H, 4.63; N, 11.70; Found: C, 36.81; H, 4.79; N, 11.49.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Bromo-2′-iodopyridinyl)]-7-azabicyclo[2-2.1]-heptane(D3.1)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(209 mg, 0.565 mmol) in isoamyl nitrite (1.2 mL) and diiodomethane (4mL) was added hydroiodic acid (0.020 mL). The reaction was allowed tostir overnight. The mixture was then poured into a solution of 1:1NH₄OH:H₂O (20 mL) and extracted with chloroform. The combined organiclayers were dried with sodium sulfate, concentrated, then the residuewas purified via flash chromatography using (CHCl₃:CH₃OH:NH₄OH/45:9:1)to give7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Bromo-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(85 mg, 31%) as a colorless solid.

¹H NMR (CDCl₃) δ (ppm) 1.45 (s, 9H), 1.50-1.65 (m, 2H), 1.70-1.90 (m,3H), 1.99 (dd, J=9.0, 12.4 Hz, 1H), 2.81 (dd, J=4.9, 8.9 Hz, 1H), 4.17(br s, 1H), 4.39 (br s, 1H), 7.79 (s, 1H, pyridyl CH), 8.18 (s, 1H,pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.2 (3C), 28.4, 29.5, 40.2, 57.0,61.6, 80.1, 120.8, 129.6, 138.2, 142.2, 147.5, 154.9.

2-exo-[5′-(3′-Bromo-2′-Iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T3e)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(85 mg, 0.177 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated K₂CO₃ solution and extractedwith methylene chloride 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using (CHCl₃:CH₃OH:NH₄OH/45:9:1) as eluent to give2-exo-[5′-(3′-Iodo-2′-iodoyridyl)]-7-azabicyclo[2.2.1]-heptane (55 mg,82%) as a colorless oil.

¹H NMR (CD₃OD) δ (ppm) 1.4-1.8 (m, 5H), 1.99 (dd, J=9.0, 12.3 Hz, 1H),2.87 (dd,J=5.4, 9.0 Hz, 1H), 3.30 (br s, 1NH), 3.61 (br s, 1H), 3.74 (brs, 1H), 8.00 (s, 1H, pyridyl CH), 8.22 (s, 1H, pyridyl CH); ¹³C NMR(CD₃OD) δ (ppm) 29.8, 31.6, 40.8, 44.4, 57.6, 63.3, 120.7,130.6, 140.0,144.4, 149.0.

2-exo-[5′-(3′-Bromo-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (T3e)Hydrochloride Monohydrate

To a stirred solution of2-exo-[5′-(3′-Bromo-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (53mg, 0.140 mmol) in ether (0.700 mL) and methanol (0.300 mL) was added asolution of 1M HCl in ether (0.600 mL) dropwise. After 30 min ofstirring the solvents were removed under reduced pressure to provide2-exo-[5′-(3′-Bromo-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride Monohydrate (57 mg, 98%) as a colorless solid.

mp 160-162° C.; Analytical Calculated for C₁₁H₁₅ON₂BrlCl: C, 30.48; H,3.49; N, 6.46; Found: C, 30.21; H, 3.37; N, 5.98.

2-exo-5′-(3′-Bromo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3c)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(199 mg, 0.538 mmol) in concentrated hydrochloric acid (2 mL) was addedsodium nitrite (700 mg, 10.1 mmol). The reaction was allowed to stir at0° C. for 15 min. Copper (1) chloride (2 g, 20.2 mmol) was then added insmall portions and stirring continued for 30 min. The mixture was thenpoured into a solution of 3:1 NH₄OH:H₂O(50 mL) and extracted withchloroform. The combined organic layers were dried with magnesiumsulfate, concentrated, then the residue was purified via flashchromatography using (CHCl₃:CH₃OH:NH₄OH/45:9:1) to give2-exo-[5′-(3′-Bromo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (58mg, 38%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.7 (m, 4H), 1.90 (dd, J=9.1, 12.3 Hz, 2H),(dd, J=4.9, 8.9 Hz, 1H), 3.58 (br s, 1H), 3.80 (br s, 1H), 8.13 (s, 1H,pyridyl CH), 8.23 (s, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 30.2,31.4, 40.4, 44.0, 56.3, 62.7, 119.9, 141.1, 143.0, 147.0, 148.0.

2-exo-[5′-(2′-Chloro-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3c)

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Amino-3′-bromopyryidyl)]-7-azabicyclo[2.2.1]-heptane(1.065 g, 3.63 mmol) was dissolved in concentrated HCl (15 mL) at 0° C.Sodium nitrite (5.0 g, 72 mmol) and CuCl (5.7 g, 57.6 mmol) were thenadded slowly to the reaction. After one hour of stirring at roomtemperature the reaction contents were poured into 1:1 mixture of water:NH₄OH and extracted with chloroform. The organic extracts were combined,dried with sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by flash chromatography using CHCl₃:CH₃OH:NH₄OH(45:9:1) as eluent to provide2-exo-[5′(2′-Chloro-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane (400mg, 53%) as a colorless oil.

mp oil ° C.; ¹H NMR (CDCl₃) δ (ppm) 1.45-1.70 (m, 5H), 1.90 (dd,J=8.9,12.1 Hz, 1H), 2.75 (dd, J=4.9. 8.9 Hz, 1H), 3,55 (s, 1H), 3.79 (s, 1H),7.22 (d, J=8.3 Hz, 1H), 7.77 (dd, J=2.5, 8.3 Hz, 1H), 8.28 (d, J=2.5 Hz,1H); ¹³C NMR (CDCl₃) δ (ppm) 30.09, 31.28, 40.27, 44.39, 56.26, 62.64,123.74, 137.59, 141.07, 148,65, 148.74.

2-exo-[5′-(3′-Bromo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3c) Hydrochloride

To a stirred solution of2-exo-[5′-(3′-Bromo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (20mg, 0.0695 mmol) in ether (0.500 mL) was added excess 1M HCl in ether(0.200 mL) dropwise. After 30 min of stirring the solvent was removedunder reduced pressure to provide2-exo-[5′-(3′-Bromo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride (25 mg, 99%) as a colorless solid.

mp 248-249° C.; Analytical Calculated for C₁₁H₁₃N₂BrCl₂: C, 40.77; H,4.04; N, 8.65; Found: C, 40.88; H, 4.09; N, 8.58.

2-exo-[5′-(3′-Bromo-2′-fluoropyridyl)]-7-azabicyclo[2.2.1]-heptane (T3b)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(68 mg, 0.184 mmol) in HF-pyridine (0.200 mL) was added a mixture ofsodium nitrite (86 mg, 1.25 mmol) and water (0.600 mL). The reaction wasallowed to heat at 80° C. for 1 h. The mixture was then poured into asolution of 1:1 NH₄OH:H₂O (20 mL) and extracted with chloroform. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography using(CHCl₃:CH₃OH:NH₄OH/45:9:1) as eluent to provide2-exo-[5′-(3′-Bromo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (17mg, 34%) as a colorless oil. ¹H NMR (CD₃OD) δ (ppm) 1.4-1.7 (m, 5H),1.90 (dd, J=9.0, 12.4 Hz, 1H), 2.73 (dd, J=5.3, 9.0 Hz, 1H), 3.52 (d,J=3.7 Hz, 1H), 3.71 (t, J=4.1 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H, pyridylCH), 8.05 (d. J=2.4 Hz, 1H, pyridyl CH); ¹³C NMR (CD₃OD) δ (ppm) 31.0,32.2, 39.4, 44.6, 58.1, 63.4, 116.4, 126.0, 132.7, 144.1, 146.0, 161.0.

2-exo-[5′-(3′-Bromo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3b) Hydrochloride

To a stirred solution of2-exo-[5′-(3′-Bromo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (51mg, 0.188 mmol) in methanol (0.50 mL) and chloroform (0.50 mL) was addedexcess 1M HCl in ether (2 mL) dropwise. After stirring for 30 min thesolvents were removed and the solid recrystallized to provide2-exo-[5′-(3′-Bromo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride (12 mg, 21%) as a colorless solid.

mp 277-282° C.; Analytical Calculated for C₁₁H₁₃N₂BrFCl: C, 42.95; H,4.26; N, 9.11; Found: C, 43.27; H, 4.61; N, 9.07.

2-exo-[5′-(2′-Hydroxy-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]hepatane(D3.2) Hydrochloride

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-hydroxy-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide complex (82 mg, 0.185 mmol) was dissolved in1,4-dioxane (2 mL). After adding a solution of 3M HCl (0.7 mL), thereaction was allowed to reflux for 30 min. The solvents were thenremoved under reduced pressure and the residue pumped overnight toprovide2-exo-[5′-(2′-hydroxy-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 0.5 Hydrate (74 mg, Quantitative) as a light brown solid.

mp 269-272° C.; Analytical Calculated for C₁₁H₁₄N₂OBrCl×0.5 H₂O: C,41.99; H, 4.81; N, 8.90; Found: C, 42.41; H, 4.86; N, 8.53.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′{3″-nitrophenyl}−2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.3; X=H; Y=NO₂)

To a resealable reaction tube under nitrogen was added7-tert-Butoxycarbonyl-2-exo-[5′-(2′-amino-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(474 mg, 1.28 mmol), Pd(oAc)₂ (23 mg, 0.102 mmol), P(O-tolyl)₃ (62 mg,0.204 mmol), sodium carbonate (275 mg, 2.59 mmol), 3-nitrophenylboronicacid (325 mg, 1.95 mmol), degassed water (1.30 mL) and DME (6.5 mL). Thereaction was heated at 80° C. for 12 h. The mixture was poured intosaturated sodium bicarbonate and extracted with ethyl acetate 3×. Theorganic layers were dried with sodium sulfate, concentrated, then theresidue was purified by flash chromatography using 1:2 hexane:ethylacetate as eluent to provide7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(328 mg, 62%) as a colorless solid.

¹H NMR (CDCl₃) δ (ppm) 1.38 (br s, 9H), 1.55 (ddd, J=8.6, 16.6, 20.7 Hz,2H), 1.72-1.90 (m, 3H), 1.98 (dd, J=9.1, 12.4 Hz, 1H), 2.82 (dd, J=4.9,8.8 Hz, 1H), 4.16 (s, 1H), 4.36 (s, 1H), 4.64 (br s, 2 NH), 7.3 7-8.35(m, 6H); ¹³C NMR (CDCl₃) δ (ppm) 28.15(3C), 28.6, 29.6, 40.30, 44.73,55.7, 60.25, 79.49, 119.10, 122.44, 123.58, 129.91, 132.22, 134.81,136.73, 140.00, 146.85, 148.61, 154.00, 154.96.

2-exo-[5′-{3′-(3″-Nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.4)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-{3′-(3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(40 mg, 0.0975 mmol) in methylene chloride (2.0 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (1.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa solution of 1:1 NH₂OH:H₂O and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(23 mg, 76%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.75 (m, 4H), 1.81 (br s, 1H), 1.90 (dd,J=8.9, 12.1 Hz, 1H), 2.75 (dd, J=5.0, 8.9 Hz, 1H), 3.56 (br s, 1H), 3.77(br s, 1H), 4.49 (br s, 2H), 7.25-8.35 (m,6 aryl CH); ¹³C NMR (CDCl₃) δ(ppm) 30.01, 31.20, 40.19, 44.54, 56.40, 63.00, 119.18, 122.50, 123.81,129.95, 133.23, 134.91, 137.22, 140.21, 147.02, 153.77.

2-exo-[5′-{3′-(3″-Nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.4) Hydrochloride

2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(23 mg, 0.148 mmol) was dissolved in 1:1 ether:methylene chloride (2 mL)and then 1M HCl in ether (1 mL) was added dropwise. The reaction wasallowed to stir for 30 min at room temperature. The solvent was removedunder reduced pressure and the remaining2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane2.25 Hydrochloride 1.25 Hydrate was pumped overnight to give (32 mg,Quantitative) as a colorless solid.

Analytical Calculated for C₁₇H_(22.75)N₄Cl2.25O_(3.25); C, 49.21; H,5.48; N, 13.50; Found: C, 49.21; H, 5.75; N, 13.19.

2-exo-[5′-{3′-(3″-Nitrophenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T4k)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(79 mg, 0.192 mmol) in concentrated hydrochloric acid (2.0 mL) was addedsodium nitrite (230 mg, 3.33 mmol). Copper (1) chloride (350 mg, 3.54mmol) was then added in small portions and stirring continued for 30 min0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O (50mL) and extracted with ethyl acetate. The combined organic layers weredried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive2-exo-[5′-(3′-{3″-Nitrophenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(44 mg, 69%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.80 (m, 5H), 1.95 (dd, J=9.0, 12.2 Hz, 1H),2.82 (dd, J=4.9, 8.9 Hz, 1H), 3.62 (br s, 1H), 3.81 (br s, 1H), 7.64 (t,J=8.1 Hz, 1H), 7.78-7.90 (m, 2H), 8.24-8.41 (m, 3H); ¹³C NMR (CDCl₃) δ(ppm)30.29, 31.50, 40.45, 44.36, 56.33, 62.78, 123.0, 124.35, 129.23,133.94, 135.54, 138.52, 139.37, 142.08, 146.72, 148.13, 148.56.

2-exo-[5′-(3′-{3″-Nitrophenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T4k) Hydrochloride

2-exo-[5′-(3′-{3″-nitrophenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptanemg, 0.133 mmol) was dissolved in 1:1 ether:methylene chloride (2 mL) andthen 1M HCl in ether (1 mL) was added dropwise. The reaction was allowedto stir for 30 min at room temperature. The solvent was removed underreduced pressure and the remaining2-exo-[5′-(3′-{3″-nitrophenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane1.5 Hydrochloride 1.75 Hydrate was pumped overnight to give (45 mg, 81%)as a colorless solid.

Analytical Calculated for C₁₇H₂₁N₃Cl_(2.5)O_(3.75); C, 49.08; H, 5.09;N, 10.10; Found: C, 49.42; H, 4.67; N, 9.62.

2-exo-[5′-(3′-{3′-Nitrophenyl}-2′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.5)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(73 mg, 0.178 mmol) in concentrated hydrobromic acid (1.2 mL) was addedsodium nitrite (250 mg, 3.33 mmol). Copper (1) chloride (1000 mg, 6.96mmol) was then added in small portions and stirring continued for 30 min0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O (50mL) and extracted with ethyl acetate. The combined organic layers weredried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive2-exo-[5′-(3′-{3″-Nitrophenyl}-2-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(23 mg, 35%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.50-1.85 (m, 4H), 1.86-2.20 (m, 2H), 2.81 (dd,J=4.9, 8.9 Hz, 1H), 3.63 (br s, 1H), 3.81 (br s, 1H), 7.63 (t, J=7.6 Hz,1H), 7.77-7.87 (m, 2H), 8.25-8.40 (m, 3H); ¹³C NMR (CDCl₃) δ (ppm) 30.5,31.5, 40.5, 44.3, 56.3, 62.7, 123.0, 124.4, 129.2, 135.6, 136.7, 138.0,139.0, 140.7, 142.2, 148.0, 149.0.

2-exo-[5′-(3′-{3″-Nitrophenyl}-2′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.5) Hydrochloride

2-exo-[5′-(3′-{3″-nitrophenyl}-2′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(23 mg, 0.0615 mmol) was dissolved in methylene chloride (1.5 mL) andthen 1M HCl in ether (1 mL) was added dropwise. The reaction was allowedto stir for 30 min at room temperature. The solvent was removed underreduced pressure and the remaining2-exo-[5′-(3′-{3″-nitrophenyl}-2′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride 0.5 Hydrate was pumped overnight to give (18 mg, 70%) as acolorless solid.

mp 196-198° C. Analytical Calculated for C₁₇H₁₇N₃ClBrO₂×0.5 H₂O: C,48.65; H, 4.32; N, 10.01; Found: C, 48.53; H, 4.35; N, 9.85.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3′-Nitrophenyl}-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(101 mg, 0.246 mmol) in methylene iodide (2.0 mL) and isoamyl nitrite(1.0 mL) was allowed to stir at room temperature for 30 min. H1 (0.009mL) was then added. After 24 h the reaction was decanted into 1:1NH₄OH:H₂O and then extracted with chloroform 3×. The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 9:1 hexane:ethyl acetate aseluent to give7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(32 mg, 25% yield) as a colorless oil.

¹H NMR (CDCl3) δ (ppm) 1.42 (s, 9H), 1.5-1.65 (m, 2H), 1.72-1.90 (m,3H), 1.95 (dd, J=8.9, 12.4 Hz, 1H), 2.72 (dd, J=4.8, 8.9 Hz, 1H), 4.16(br s, 1H), 4.35 (br s, 1H), 7.33 (d, J=2.4 Hz, 1H), 7.58 (t, J=8.0 Hz,1H), 7.75 (d, J=2.4 Hz, 1H), 8.08 (d, J=7.9 Hz, 1H), 8.20 (d, J=7.9 Hz,1H), 8.63 (t, J=1.9 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 28.23 (3C), 28.82,29.48, 39.73, 44.43, 56.00, 62.02, 79.94, 122.42, 123.42, 124.81,128.43, 129.04, 132.15, 134.59, 138.16, 140.77, 148.23, 155.21, 162.75.

2-exo-[5′(3′-{3″-Nitrophenyl}-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.6)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-nitrophenyl}-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(32 mg, 0.202 mmol) in methylene chloride (1.5 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (1.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa 1:1 NH₄OH:H₂O solution and extracted with chloroform 3×. The combinedorganic extracts were dried with sodium sulfate, concentrated, then theresidue was purified by flash chromatography using CHCl₃:CH₃OH:NH₄OH(45:9:1) as eluent to give2-exo-[5′-(3′-{3″-nitrophenyl}-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(17 mg, 66%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.75 (m, 4H), 1.86 (dd, J=8.8, 12.3 Hz, 1H),2.04 (br s, 1H), 2.63 (dd, J=4.8, 8.8 Hz, 1H), 3.59 (br s, 1H), 3.79 (brs, 1H), 7.40 (d, J=2.4 Hz, 1H), 7.57 (t, J=8.0Hz, 1H), 7.83 (d, J=2.4Hz,1 CH), 8.08 (d, J=7.8Hz, 1H), 8.17 (d, J=7.8 Hz, 1H), 8.61 (t, J=1.9 Hz,1H); ¹³C NMR (CDCl₃) δ (ppm) 30.11, 30.95, 39.40, 44.07, 56.36, 62.53,122.31, 123.46, 125.58, 128.05, 129.02, 132.0, 134.59, 138.31, 141.63,148.21, 162.60.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-methoxyphenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(D3.3; X=H; Y=CH₃O)

To a resealable reaction tube under nitrogen was added7-tert-Butoxycarbonyl-2-exo-[5′-(2′-amino-3′-bromopyridinyl)]-7-azabicyclo[2.2.1]-heptane(997 mg, 2.696 mmol), Pd(OAc)₂ (55 mg, 0.245 mmol), P(o-tolyl)₃ (139 mg,0.457 mmol), sodium carbonate (275 mg, 5.47 mmol),3-methoxyphenylboronic acid (649 mg, 4.27 mmol), degassed water (2.6 mL)and DME (13 mL). The reaction was heated at 90° C. for 12 h. The mixturewas poured into saturated sodium bicarbonate and extracted with ethylacetate 3×. The organic layers were dried with sodium sulfate,concentrated, then the residue was purified by flash chromatographyusing 1:2 hexane:ethyl acetate as eluent to provide7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-methoxyphenyl}-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(959 mg, 90%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.38 (s, 9H), 1.45-1.65 (m, 3H), 1.7-2.0 (m, 3H),2.78 (dd, J=4.9, 7.7 Hz, 1H), 3.82 (s, 3H), 4.16 (s, 1H), 4.34 (s, 1H),4.66 (s, 2H), 6.85-7.07 (m, 3H), 7.28-7.40 (m, 2H), 7.92 (s, 1H); ¹³CNMR (CDCl₃) δ (ppm) 28.11(3C), 28.64, 29.66, 40.12, 44.79, 55.11, 55.66,62.10, 79.29, 113.11, 114.07, 120.83, 121.43, 129.87, 131.54, 136.45,139.47, 145.51, 154.27, 154.86, 159.84.

2-exo-[5′-(3′-{3″-Methoxyphenyl}-2′-chloropyridinyl)]7-azabicyclo[2.2.1]-heptane(T4h)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-{3″-methoxyphenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(167 mg, 0.422 mmol) in concentrated hydrochloric acid (2.0 mL) wasadded sodium nitrite (440 mg, 6.38 mmol). Copper (1) chloride (630 mg,6.36 mmol) was then added in small portions and stirring continued for30 min 0° C. The mixture was then poured into a solution of 1:1NH₄OH:H₂O (50 mL) and extracted with ethyl acetate. The combined organiclayers were dried with magnesium sulfate, concentrated, then the residuewas purified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1)to give2-exo-[5′-(3′-{3″-Methoxyphenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(83 mg, 63%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.8 (m, 4H), 1.8-2.05 (m, 2H), 2.81 (dd,J=5.0, 8.8 Hz, 1H), 3.62 (br s, 1H), 3.78 (br s, 1H), 3.84 (s, 3H),6.8-7.1 (m, 3H), 7.31 (t, J=7.9 Hz, 1H), 7.76 (s, 1H), 8.34 (s, 1H); ¹³CNMR (CDCl₃) δ (ppm) 29.98, 31.25, 40.19, 44.45, 55.25, 56.35, 62.65,113.49, 115.06, 121.66, 129.21, 136.09, 138.50, 139.00, 141.24, 146.89,147.41, 159.21.

Experimental Procedures for Scheme D4 Shown in FIG. 92-exo-[5′-(3′-Amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3j)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyt)]-7-azabicyclo[2.2.1]-heptane(130 mg, 0.401 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated NaHCO₃ solution (at thispoint much material was spilled) and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography using 45 CMA aseluent to give2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (17mg, 19%) as a colorless solid.

mp 113-115° C.; ¹H NMR (CDCl₃) δ (ppm) 1.4-1.8 (m, 1H), 1.88 (dd, J=9.0,11.9 Hz, 1H), 2.70 (dd, J=4.9, 8.6 Hz, 1H), 3.55 (br s, 1H), 3.77 (br s,1H), 4.06 (br s, 2H), 7.20 (s, 1H, pyridyl CH), 7.67 (s, 1H, pyridylCH); ¹³C NMR (CDCl₃) δ (ppm) 30.01, 31.36, 40.36, 44.38, 56.35, 62.79,121.21, 134.74, 137.89, 139.24, 142.50.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(130 mg, 0.401 mmol) in methylene iodide (2.0 mL) and isoamyl nitrite(1.0 mL) was allowed to stir at room temperature for 30 min. HI (0.012mL) was then added. After 3 h the reaction was decanted into 1:1NH₄OH:H₂O and then extracted with chloroform 3×. The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 9:1 hexane:ethyl acetate aseluent to give2-exo-[5′-(3′-Iodo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (74mg, 42%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.46 (s, 9H), 1.52-1.62 (m, 2H), 1.70-1.92 (m,3H), 1.99 (dd, J=1.7, 10.8 Hz, 1H), 2.82 (dd, J=4.8, 8.8 Hz, 1H), 4.17(br s, 1H), 4.39 (br s, 1H), 8.12 (s, 1H, pyridyl CH), 8.23 (s, 1H,pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.29 (3C), 28.72, 29.66, 40.28,44.44, 55.8, 61.69, 80.05, 94.73, 141.45, 147.21, 147.73, 152.16,154.84.

2-exo-[5′-(3′-Iodo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3m)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodo-2′-chloropyridinyl)]-7-azabicyclo[2-2.1]-heptane(56 mg, 0.129 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated NaHCO₃ solution andextracted with chloroform 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-Iodo-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (39mg, 91%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.42-1.70 (m, 5H), 1.70-1.92 (m, 3H), 1.89 (dd,J=9.1, 12.1 Hz, 1H), 2.69 (dd,J=4.8, 8.8 Hz, 1H), 3.55 (brs, 1H), 3.79(brs, 1H), 8.25 (s, 1H, pyridyl CH), 8.31 (s, 1H, pyridyl CH); ¹³C NMR(CDCl₃) δ (ppm) 30.28, 31.42, 40.39, 43.97, 56.25, 62.64, 94.60, 142.73,147.73, 147.90, 151.69.

2-exo-[5′-(2′,3′-Dichloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T3h)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(92 mg, 0.284 mmol) in concentrated hydrochloric acid (2 mL) was addedsodium nitrite (600 mg, 8.7 mmol). Copper (1) chloride (600 mg, 6.1mmol) was then added in small portions and stirring continued for 30 min0° C. The mixture was then poured into a solution of 1:1 NH₄OH:H₂O (50mL) and extracted with ethyl acetate. The combined organic layers weredried with magnesium sulfate, concentrated, then the residue waspurified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1) togive 2-exo-[5′-(2′,3′-Dichloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(51 mg, 74%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.75 (m, 5H), 1.90 (dd, J=8.9, 12.0 Hz, 1H),2.73 (dd, J=4.8, 8.8 Hz, 1H), 3.56 (br s, 1H), 3.80 (br s, 1H), 7.98 (d,J=2.0 Hz, 1H), 8.19 (d,J=2.0 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 30.32,31.42, 40.42, 44.08, 56.23, 62.68, 130.05, 137.70, 143.07; 146.35(2C).

2-exo-[5′-(2′,3′-Dichloropyridinyl)]-7-azabicyclo [2.2.1]-heptane (T3h)Hydrochloride

2-exo-[5′-(2′,3′-Dichloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (51 mg,0.168 mmol) was dissolved in ether (2 mL) and then 1M HCl in ether (1mL) was added dropwise. The reaction was allowed to stir for 30 min atroom temperature. The solvent was removed under reduced pressure and theremaining2-exo-[5′-(2′,3′-Dichloropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride was pumped overnight to give (52 mg, 89%) as a colorlesssolid.

mp 240-241° C.; Analytical Calculated for C₁₁H₁₃N₂Cl₃; C, 47.25; H,4.69; N, 10.02; Found: C, 47.34; H, 4.76; N, 9.82.

2-exo-[5′-(2′-Chloro-3′-fluoropyridinyl)]-7-azabicyclo [2.2.1]-heptane(T3k)

To a solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(59 mg, 0.182 mmol) in 70% HF-pyridine (1.1 mL) inside a plasticreaction vessel at 0° C. was added sodium nitrite (100 mg, 1.4 mmol).Stirring continued for 30 min before being heated at 100° C. for anadditional 30 min. The mixture was then poured into a solution of 1:1NH₄OH:H₂O (50 mL) and extracted with ethyl acetate. The combined organiclayers were dried with magnesium sulfate, concentrated, then the residuewas purified via flash chromatography using CHCl₃:CH₃OH:NH₄OH (45:9:1)to give2-exo-[5′(2′-Chloro-3′-Fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (30mg, 73%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.65 (m, 4H), 1.74 (br s, 1H), 1.91 (dd,J=8.9, 12.2 Hz, 1H), 2.77 (dd, J=4.8, 8.7 Hz, 1H), 3.57 (br s, 1H), 3.79(br s, 1H), 7.75 (dd, J_(HF)=1.9, 9.6 Hz, 1H), 8.09 (d, J_(HF)=1.5 Hz,1H); ¹³C NMR (CDCl₃) δ (ppm) 30.27, 31.39, 40.48, 44.07, 56.26, 62.78,123.47 (J_(CF)=18.8 Hz), 136.15 (J_(CF)=21.2 Hz), 143.59 (J_(CF)=4.8Hz), 144.10 (J_(CF)=2.5 Hz), 154.69 (J_(CF)=260 Hz).

2-exo-[5′-(2′-Chloro-3′-fluoropyridinyl)]-7-azabicyclo [2.2.1]-heptane(T3k) Hydrochloride

2-exo-[5′-(2′-Chloro-3′-fluoropyridinyl)]-7-azabicyclo(2.2.1]-heptane(30 mg, 0.132 mmol) was dissolved in ether (2 mL) and then 1M HCl inether (1 mL) was added dropwise. The reaction was allowed to stir for 30min at room temperature, The solvent was removed under reduced pressureand the remaining2-exo-[5′-(2′-Chloro-3′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride was pumped overnight to give (31 mg, 89%) as a colorlesssolid.

mp 204-206° C.; Analytical Calculated for C₁₁H₁₃N₂FCl₁₂; C, 50.21; H,4.98; N, 10.65; Found: C, 49.98; H, 4.94; N, 10.51.

2-exo-[5′-(2′-Chloro-3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3m) Hydrochloride

2-exo-[5′-(2′-Chloro-3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (39mg, 0.117 mmol) was dissolved in ether/methylene chloride (1 mL+1 mL)and then 1M HCl in ether (1 mL) was added dropwise. The reaction wasallowed to stir for 30 min at room temperature. The solvent was removedunder reduced pressure and the remaining2-exo-[5′-(2′-Chloro-3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride was pumped overnight to give (42 mg, 97%) as a colorlesssolid. mp 223-224° C., Analytical Calculated for C₁₁H₁₃N₂lCl₂; C, 35.61;H, 3.53; N, 7.55; Found: C, 35.70; H, 3.59; N, 7.41.

2-exo-[5′-(2′,3-Difluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T3g)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(69 mg, 0.224 mmol) in 70% HF-pyridine (2 mL) inside a plastic reactionvessel was allowed to stir at 0° C. for 15 min. Sodium nitrite (160 mg,2.32 mmol) was then added in small portions and stirring continued atroom temperature for 1 h. The mixture was then poured into a solution of1:1 NH₄OH:H₂O(50 mL) and extracted with ethyl acetate. The combinedorganic layers were dried with magnesium sulfate, concentrated, then theresidue was purified via flash chromatography using CHCl₃:CH₃OH:NH₄OH(45:9:1) to give2-exo-[5′-(2′,3′-Difluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (27 mg,57%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.5-1.8 (m, 5H), 1.91 (dd, J=8.9. 12.1 Hz, 1H),2.77 (dd, J=4.7, 8.8 Hz, 1H), 3.56 (br s, 1H), 3.79 (br s, 1H),7.79-7.88 (m, 2H); ¹³C NMR (CDCl₃) δ (ppm) 30.31, 31.40, 40.59, 43.99,56.25, 62.80, 125.70 (J_(CF)32 12.3 Hz), 139.70 (J_(CF)32 5.2, 12.5 Hz),142.38 (J_(CF)32 3.8 Hz), 145.27 (J_(CF)32 27.8, 260 Hz), 150.48(J_(CF)32 13.9, 236 Hz).

2-exo-[5′-(2′,3′-Difluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (T3g)Hydrochloride

2-exo-[5′-(2′,3′-Difluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (27 mg,0.128 mmol) was dissolved in ether (2 mL) and then 1M HCl in ether (1mL) was added dropwise. The reaction was allowed to stir for 30 min atroom temperature. The solvent was removed under reduced pressure and theremaining2-exo-[5′-(2′,3′-Difluoropyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride was pumped overnight to give (31 mg, 98%) as a colorlesssolid.

mp 227-228° C.; Analytical Calculated for C₁₁H₁₃N₂F₂Cl₂; C, 53.56; H,5.31; N, 11.36; Found: C, 53.33; H, 5.33; N, 11.12.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-amino-2′-fluoropyridinyl)]7-azabicyclo[2.2.1]-heptane(105 mg, 0.540 mmol) in methylene iodide (2.0 mL) and isoamyl nitrite(1.0 mL) was allowed to stir at room temperature for 30 min. HI (0.012mL) was then added. After 24 h the reaction was decanted into 1:1NH₄OH:H₂O and then extracted with chloroform 3×. The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 9:1 hexane:ethyl acetate aseluent to give2-exo-[5′-(3′-iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (49mg, 22%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.46 (s, 9H), 1.35-1.90 (m, 5H), 2.00 (dd, J=9.0,12.4 Hz, 1H), 2.85 (dd, J=4.8, 8.9 Hz, 1H), 4.16 (br s, 1H), 4.39 (br s,1H), 8.01 (s, 1H, pyridyl CH), 8.14 (dd, J_(HF)=2.0, 8.0 Hz, 1H); ¹³CNMR (CDCl₃) δ (ppm) 28.27 (3C), 28.70, 29.60, 40.39, 44.37, 55.82,61.80, 80.02, 140.82 (J_(CF)=5.0 Hz), 145.62 (J_(CF)=13 Hz), 148.48,154.89, 158.91, 162.62.

2-exo-[5′-(3′-Iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3i)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(49 mg, 0.117 mmol) in methylene chloride (2.0 mL) was stirred at 0° C.for 15 min. Trifluoroacetic acid (2.0 mL) was then added and allowed tostir at room temperature for 30 min. The reaction was then decanted intoa saturated NaHCO₃ solution and extracted with chloroform 3×. Thecombined organic extracts were dried with sodium sulfate, concentrated,then the residue was purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to give2-exo-[5′-(3′-Iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane (33mg, 89%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.4-1.75 (m, 5H), 1.89 (dd, J=9.0, 12.1 Hz, 1H),3H), 2.71 (dd, J=4.9, 8.8 Hz, 1H), 3.55 (br s, 1H), 3.79 (br s, 1H),8.03 (s, 1H, pyridyl CH), 8.33 (dd, J=2.1, 8.2 Hz, 1H, pyridyl CH); ¹³CNMR (CDCl₃) δ (ppm)30.30, 31.43, 40.56, 43.93, 56.28, 62.72, 142.09(J=4.9 Hz), 145.67 (J=12.9 Hz), 149.03, 158.73, 162.44.

2-exo-[5′-(3′-Iodo-2′-fluoropyridinyl)]-7-azabicyclo[2.2.1]-heptane(T3i) Hydrochloride

2-exo-[5′-(2′-Fluoro-3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (33mg, 0.128 mmol) was dissolved in ether (2 mL) and then 1 M HCl in ether(1 mL) was added dropwise. The reaction was allowed to stir for 30 minat room temperature. The solvent was removed under reduced pressure andthe remaining2-exo-[5′-(2′-Fluoro-3′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride was pumped overnight to give (36 mg, 98%) as a colorlesssolid.

mp 238-240° C.; Analytical Calculated for C₁₁H₁₃N₂lFCl; C, 37.26; H,3.70; N, 7.90; Found: C, 37.42; H, 3.71; N, 7.78.

Experimental Procedures for Scheme 1 Shown in FIG. 122-Amino-5-iodo-4-picoline (2)

Compound 1 (27.0 g, 0.25 mol) was mixed with periodic acid (11.4 g,0.050 mol), HOAc (150 mL), H₂SO₄ (4.5 mL) and H₂O (30 mL). Iodine (25.4g (0.10 mol) was added and the reaction mixture was stirred at 80° C.for 4 h. The mixture was cooled and poured into H₂O containing 40 g ofNa₂S₂O₃. The reaction mixture was decanted from a reddish oil and thefiltrate was basified with 50% NaOH. The resulting solids were extractedwith diethyl ether (2×300 mL). The ether layer was separated, dried(Na₂SO₄) and concentrated. The solids were recrystallized from EtOH/H₂Oto afford 2 (41.8 g, 71%) as a tan solid; ¹H NMR (CDCl₃) δ 2.23 (s, 3H),4.35 (br s, 2H), 6.46 (s, 1H), 8.27 (s, 1H). Anal. (C₆H₇IN₂) C, H, N.

Compound (3)

To 2 (29.6 g, 0.13 mol) in acetone (200 mL) was addedmeta-chloroperbenzoic acid ( 50-55%, 48.3 g) in acetone (100 mL). Thereaction was stirred at room temperature for 90 min and thenconcentrated in vacuo. The residue was taken up in CHCl₃ and stirredwhile adding 2M ethereal HCl (100 mL). The mixture was filtered and thesalt was recrystallized from EtOH/diethyl ether to yield 3 (30.8 g, 85%)as a tan solid: mp 198-200° C.; ¹H NMR (DMSO-d₆) δ 2.34(s, 3H), 7.08 (s,1H), 8.39 (br s, 3H), 8.74 (s, 1H). Anal. (C₆H₈ClIN₂O) C, H, N.

2-Acetamido-4-chloromethyl-5-iodopyridine (4)

Acetic anhydride (2.4 g, 0.023 mol) was added to a heterogeneous mixtureof 3 (3.0 g, 0.0105 mol) in dioxane (50 mL). The reaction was stirred atreflux for 17 h. The dark brown mixture was concentrated in vacuo andthe residue was partitioned between 5% NaHCO₃ and CH₂Cl₂. The organiclayer was separated, washed with brine, separated, dried (Na₂SO₄) andconcentrated. The residue was taken up in EtOAc and ran through a plugof silica gel. The filtrate was concentrated to get 2.9 g of a tansolid. The crude product was purified by flash chromatography on silicagel using 75% hexane/acetone), as the eluent, to yield 4 (1.81 g, 56%)as a beige solid: mp 173-174° C.; ¹H NMR (CDCl₃) δ 2.22 (s, 3H), 4.57(s, 2H), 7.98 (br s, 1H), 8.37 (s, 1H), 8.50 (s, 1H). Anal. (C₈H₈ClIN₂O)C, H, N.

7-Azabicyclo[2.2.1]-hept-2-ene (5)

To 7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene¹ (C4b; 3.9 g,0.02 mol) in CHCl₃ (150 mL) was added iodotrimethylsilane (4.84 g, 0.024mol). The mixture was stirred at room temperature for 1 h. The reactionwas quenched with MeOH (3.1 g, 0.097 mol) and concentrated. The residuewas triturated with ether to give 5 (3.26 g, 73%) as a tan solid: mp184-185° C.; ¹H NMR (CDCl₃) δ 1.45 (dd, 2H), 2.42 (m, 2H), 4.90 (s, 2H),6.40 (s, 2H), 7.95 (br s, 1H). Anal. (C₆H₁₀N) C, H, N.

¹Brieaddy, L. E.; Liang, F.; Abraham, P.; Lee, J. R.; Carroll, F. I. NewSynthesis of 7-(tert-Butoxycarbonyl)-7-azabicyclo[2.2.1]hept-2-ene. AKey Intermediate in the Synthesis of Epibatidine and Analogs. Tet.Letters. 1998, 39, 5321-5322.

Compound (6)

To NaOMe (0.26 g, 0.0045 mol) in MeOH (50 mL) was added 5 (1.0 g, 0.0045mol) followed by compound 4 (1.29 g, 0.0044 mol). The reaction wasstirred at reflux for 18 h then concentrated in vacuo. The solid residuewas triturated with CHCl₃, filtered and concentrated. The solids werepurified by silica gel column chromatography using EtOAc/hexane (1:1)eluent to give 6(0.50 g, 43%) as a beige solid: mp 130-132° C.; ¹H NMR(CDCl₃) δ 1.03 (m, 2H), 1.93 (d, 2H), 2.20 (s, 3H), 3.34 (s, 2H), 3.88(s, 2H), 6.05 (s, 2H), 8.00 (s, 1H), 8.34 (s, 1H), 8.44 (s, 1H). Anal.(C₁₄H₁₆IN₃O) C, H, N.

Compound (7)

To DMF (10 mL) in a closed reaction vessel was added compound 6, (1.60g, 0.0043 mol), KO₂CH (0.36 g, 0.0043 mol), tetrabutylammonium chloride(0.31 g, 0.0043 mol), and palladium(II)acetate (0.047 g, 0.00021 mol).The reaction was stirred at 90° C. for 19 h, cooled, brine (100 mL) andEtOAc (100 mL) were added followed by NH₄OH (50 mL). The mixture wasfiltered; the organic layer was separated, washed with brine, dried(Na₂SO₄) and concentrated to give solids. The solids were purified bysilica gel column chromatography using 80 CMA(CHCl₃:CH₃OH:NH₄OH/40:9:1):hexane:EtOAc (2:1:1) as the eluent to afford7 (0.45 g, 45%) as a beige solid: mp 204-205° C.; ¹H NMR (CDCl₃) δ 1.34(m, 1H), 1.48 (m,2H), 1.88 (m, 3H), 2.18 (s, 3H), 2.87 (d, 1H), 3.09 (d,1H), 3.48 (t, 1H), 3.95 (d, 1H), 4.38 (d, 1H), 7.92 (s, 1H), 7.99 (s,1H), 8.45 (br s, 1H). Anal. (C₁₄H₁₇N₃O.1/3H₂O) C, H, N.

Compound (8)

Compound 7 (1.10 g, 0.0045 mol) was stirred at reflux in 3N HCl (400 mL)for 7 h. The reaction was cooled, basified with solid NaOH and extractedwith CHCl₃ (2×200 mL), washed with brine, separated and dried (Na₂SO₄)to yield 8 (0.82 g, 90%) as a cream colored solid: mp 149-152° C.; mp(HCL salt): 283-286° C.; ¹H NMR (base, CDCl₃) δ 1.46-1.88 (m, 6H), 2.81(d, 11H), 3.07 (d, 1H), 3.44 (t, 1H), 3.84 (d, 1H), 4.23 (d, 1H), 4.29(br s, 2H), 6.24 (s, 1H), 7.68 (s, 1H). Anal. (Di-HCl salt)(C₁₂H₁₇CIN₃.H₂O) C, H, N.

Compound (9)

NaNO₂ (3.1 g, 0.045 mol) was added to compound 8 (0.65 g, 0.0032 mol) in12N HCl (20 mL) at ice bath temperatures. The reaction was stirred atice bath temperatures for 30 min then at room temperature for 2 h. Themixture was added to NE₄OH (40 mL), extracted with CHCl₃ (2×100 mL),separated, dried (Na₂SO₄) and concentrated. The residue was purified bysilica gel column chromatography using 80 CMA:(CHCl₃:CH₃OH:NH₄OH/40:9:1) hexane:EtOAc (2:1:1) as the eluent to afford9 (0.20 g, 28%) as a beige solid: mp 138-139° C.; ¹H NMR (CDCl₃) δ1.34-1.95 (m, 6H), 2.92 (d, 1H), 3.08 (d, 1H), 3.49 (t, 1H), 3.98 (d,1H), 4.31 (d, 1H), 7.04 (s, 1H), 8.00 (s, 1H). Anal. (C₁₂H₁₃ClN₂) C, H,N.

Experimental Procedures for Scheme 2 Shown in FIG. 132-Amino-5-iodo-6-picoline (11)

Compound 11 was prepared as shown in Scheme 1 to afford a 49% yield ofsolids: mp 100-102° C.; ¹H NMR (CDCl₃) δ 2.54 (s, 3H), 4.54 (br s, 2H),6.17 (d, 1H), 7.66 (d, 1H).

Compound (12)

The title compound was prepared following the same procedure as shown inScheme 1 to yield a copper colored solid. NMR consistent for assignedstructure.

2-Acetamido-6-chloromethyl-5-iodopyridine (13)

The same procedure as in Scheme 1 afforded an 82% yield of 13; ¹H NMR(CDCl₃) δ 2.21 (s, 3H), 4.71 (s, 2H), 7.91 (br s, 1H), 7.94 (s, 1H),8.04 (d, 1H).

Compound (14)

The same procedure as in Scheme 1 gave an 81% yield of 14. ¹H NMR(CDCl₃) δ 0.96 (d, 2H), 1.82 (d, 2H), 2.10 (s, 3H), 3.55 (s, 2H), 3.91(s, 2H), 6.04 (s, 2H), 7.82 (d, 1H), 7.98 (d, 1H), 8.84 (br s, 1H).

Compound (15)

The same procedure as in Scheme 1 gave a 43% yield of 15; ¹H NMR (CDCl₃)δ 1.33 (m, 1H), 1.51 (m, 2H), 1.88 (m, 3H), 2.16 (s, 3H), 2.86 (d, 1H),3.18 (d, 1H), 3.53 (t, 1H), 3.89 (d, 1H), 4.28 (d, 1H), 7.24 (d, 1H),7.87 (d, 1H), 8.61 (br s, 1H).

Compound (16)

The same procedure as in Scheme 1 afforded 61% yield of 16 as a whitesolid: mp (HCl salt) 201-206° C.; ¹H NMR (base, CDCl₃) δ 1.29-1.86 (m,6H), 2.73 (d, 1H), 3.16 (d, 1H), 3.49 (t, 1H), 3.85 (d, 1H), 4.26 (d,1H), 4.29 (br s, 2H), 6.21 (d, 1H), 7.01 (d, 1H). Anal. (Di-HCl salt)(C₁₂H₁₇ClN₃.1 3/4H₂O) C, H, N.

Compound (17)

The same procedure as in Scheme 1 gave a 32% yield of 17 as a whitesolid: mp 127-129° C.; ¹H NMR (CDCl₃) δ 1.33-1.89 (m, 6H), 2.88 (d, 1H),3.17 (d, 1H), 3.54 (t, 1H), 3.98 (d, 1H), 4.41 (d, 1H), 7.04 (d, 1H),7.21 (d, 1H). Anal. (C₁₂H₁₃ClN₂.1/4H₂O) C, H, N.

Experimental Procedures for Scheme 3 Shown in FIG. 14 Compound (20)

To DMF (20 mL) in a closed reaction vessel was added compound 18(2.0 g,0.018 mol), compound 19 (7.9 g, (0.036 mol), KO₂CH (3.0 g, 0.036 mol),tetrabutylammonium chloride (1.3 g, 0.0045 mol), and palladium(II)acetate (0.26 g, 0.0012 mol). The reaction was stirred at 110° C.for 24 h, cooled, then brine (100 mL) and EtOAc (100 mL) were added. Themixture was filtered; the organic layer was separated, washed withbrine, dried (Na₂SO₄) and concentrated to give an orange oil. The oilwas purified by silica gel chromatography using 80 CMA:(CHCl₃:CH₃OH:NH₄OH/40:9:1) hexane: EtOAC,then 80 CMA:EtOAC as eluents toafford 3 (3.0 g, 82%) as a white solid: mp 159-160° C.; ¹H NMR (MeOD) δ1.33-2.07 (m, 8H), 2.60 (m, 1H), 4.12 (m, 1H), 6.53 (d, 2H), 7.35 (dd,2H), 7.73 (d, 1H). Anal. (C₁₂H₁₆N₂O.1/4H₂O) C, H, N.

Compound (21)

Compound 20 (4.0 g, 0.019 mol) was added to ice-chilled 12N HCl (60 mL)followed by NaNO₂ (24.3 g, 0.35 mol) in portions over a 40 min period.The reaction was removed from the ice bath and allowed to stir at roomtemperature for 1 h then added to NH₄OH (300 mL). The mixture wasextracted with CHCl₃, dried (Na₂SO₄) and concentrated in vacuo to yield4 (3.84 g, 73%) as an orange oil. A C, H, N analytical sample wasprepared by dissolving the free base in ether and adding ethereal HCl togive a light yellow solid: mp 114-115° C.; ¹H NMR (CDCl₃, base) δ1.36-2.20 (m, 8H), 2.76 (m, 1H), 4.21 (s, 1H), 7.24 (d, 1H), 7.50 (dd,1H), 8.23 (d, 1H). Anal. (C₁₂H₁₅ClNO.1/4H₂O) C, H. N.

Compound (22)

To SO₃·pyridine complex (2.2 g, 0.014 mol) in DMSO was added compound 21(1.04 g, 0.0046 mol) and Et₃N (1.4 g, 0.014 mol) in a water bath (8-10°C.). The reaction was stirred for 2.5 h, added to brine (300 mL), andextracted with EtOAc. The EtOAc layer was separated, dried (Na₂SO₄) andconcentrated to give an orange oil. The oil was purified by silica gelchromatography using 70% hexane/EtOAc to yield 5 (0.51 g, 50%) as awhite solid: mp 63-64° C.; ¹H NMR (CDCl₃) δ 1.66-2.27 (m, 8H), 3.06 (m,1H), 7.25 (d, 1H), 7.43 (dd, 1H), 8.19 (d, 1H). Anal. (C₁₂H₁₂ClNO) C, H,N.

Compound (23)

Compound 22 (1.5 g, 0.0067 mol) and benzylamine (0.73 g, 0.0067 mol)were dissolved in benzene (120 mL) and heated to reflux in a Dean Starktrap for 68 h. The reaction mixture was concentrated to give an orangeoil. This oil was dissolved in MeOH (15 mL) and NaCNBH3 (0.30 g, 0.005mol) in MeOH (15 mL) was then added. The reaction was stirred for 21 hand 6N HCl was added until acid to litmus paper. The mixture wasconcentrated in vacuo and the residue was partitioned between 5NNaOH/EtOAc. The organic layer was separated, dried (Na₂SO₄), andconcentrated to give an oil which was chromatographed on silica gelusing 95% toluene/EtOAc as the eluent to afford 6 (1.17 g, 55%) as acolorless oil. A C,H,N analytical sample was prepared by dissolving thefree base in ether and adding ethereal HCl to give solids which werecrystallized from MeOH/EtOAc mixtures to afford a white solid: mp232-234° C.; ¹H NMR (DMSO-d₆) δ 1.35-1.62 (m, 5H), 2.13 (m, 2H), 2.34(m, 1H), 3.09 (m, 3H), 4.04 (m, 2H), 7.39-7.49 (m, 6H), 7.90 (d, 1H),8.45 (s, 1H), 8.73 (br s, 1H), 9.03 (br s, 1H). Anal. (C₁₉H₂₂Cl₂N₂) C,H, N.

Compound (24)

In the chromatography of 23, compound 24 (0.070 g, 4%) was also isolatedas an oil. The oil was converted to its HCl salt: mp 246-249° C.; ¹H NMR(base, CDCl₃) δ 1.29-1.32 (m, 3H), 1.56 (m, 1H), 1.70-1.96 (m, 3H), 2.10(s, 2H), 2.65 (m, 1H), 2.96 (s, 1H), 3.67 (s, 2H), 7.09-7.32 (m, 7H),8.13 (s, 1H).

Compound (25)

Compound 22 (1.96 g, 0.009 mol), NH₂OH HCl (1.0 g, 0.015 mol) and K₂CO₃(2.1 g, 0.015 mol) were stirred in EtOH (75 mL) at 35° C. for17 h. Thereaction was concentrated and the residue was partitioned betweenEtOAc/H₂O. The organic layer was separated, washed with brine,separated, dried (Na₂SO₄) and concentrated to get solids. The solidswere recrystallized from MeOH/H₂O mixtures to give 25 (1.90 g, 89%) as awhite solid: mp 162-163° C.; ¹H NMR (CDCl₃) δ 1.58-1.68 (m, 3H), 1.93(m, 2H), 2.12 (m, 1H), 2.63 (m, 1H), 2.95 (m, 1H), 3.33 (m, 1H), 7.44(d, 1H), 7.56 (d, 1H), 8.24 (s, 1H). Anal. (C₁₂H₁₃ClN₂O) C, H, N.

Compound (26)

Compound 22 (2.0 g, 0.009 mol), CH₃ONH₂ HCl (1.2 g, 0.0145 mol) andK₂CO₃ (2.0 g, 0.0145 mol) were stirred in EtOH (80 mL) at 40° C. for 24h. The reaction was concentrated and the residue was partitioned betweenEtOAc/H₂O. The organic layer was separated, washed with brine,separated, dried (Na₂SO₄) and concentrated to produce compound 26 (1.90g, 84%) as a yellow, oil. The oil was converted to its HCl salt: mp97-99° C.; ¹H NMR (base, CDCl₃) δ 1.57-2.12 (m, 6H), 2.61 (m, 1H), 2.93(m, 1H), 3.12 (m, 1H), 7.25 (d, 1H), 7.52 (d, 1H), 8.22 (s, 1H). Anal.(C₁₃H₁₆Cl₂N₂O) C, H, N.

Compound (27)

Diborane (1M, 19.2 mL, 0.0192 mol) was added to an ice chilled solutionof compound 26 (1.2 g, 0.0048 mol) in THF (15 mL). After addition revedice bath and heated reaction at reflux for a period of 2 h. Reactionmixture was then chilled to 0° C. and H₂O (5 mL) and 25% NaOH (5 mL)were added. The mixture was reluxed for 1 h and concentrated in vacuo.The residue was partitioned between brine and ether. The ether layer wasseparated, dried (Na₂SO₄) and concentrated to yield a yellow oil. Theoil was purified by silica gel column chromatography using90%CH₂Cl_(2/)MeOH as eluent to afford 27 (0.40 g, 32%) as an oil. Theoil was converted to its HCl salt: mp 222-223° C.; ¹H NMR (DMSO-d₆) δ1.35 (m, 2H), 1.72 (m, 2H), 2.09 (m, 2H), 2.31 (m, 1H), 2.85 (s, 1H),2.85 (t, 1H), 3.03 (m, 1H), 7.44 (d, 1H), 7.79 (d, 1H), 7.96 (br s, 3H),8.35 (s, 1H). Anal. (C₁₂H₁₆Cl₂N₂O) C, H, N.

Compound (28)

Compound 22 (1.0 g, 0.0045 mol) was dissolved in MeOH (15 mL) andNaCNBH₃ (0.21 g, 0.0034 mol) in MeOH (15 mL) was then added. Thereaction was stirred for 17 h and 6N HCl was added until acid to litmuspaper. The organic layer was separated, dried (Na₂SO₄), and concentratedto give an oil which was was partitioned between 5N NaOH/EtOAc. Theorganic layer was separated, dried (Na₂SO₄), and concentrated to give anoil which was chromatographed on silica gel using 70%hexane/EtOAC aseluent to afford 28 (0.28 g, 28%) as a white solid; mp 97-99° C.; ¹H NMR(CDCl₃) δ 1.21-2.28 (m, 8H), 2.87 (m, 1H), 4.12 (s, 1H), 7.19 (d, 1H),7.74 (dd, 1H), 8.31 (s, 1H). Anal. (C₁₂H₁₄ClNO) C, H, N.

^(a)Story, P. 7-Substituted Norbomadienes. J. Org. Chem. 1961, 26,287-290.

Experimental Procedures for Scheme 4 Shown in FIG. 15 Compound (29)

To DMF (10 mL) in a closed reaction vessel was added compound 2, (3.60g, 0.015 mol), compound C4b (1.5 g, 0.0077 mol), KO₂CH (1.30 g, 0.015mol), tetrabutylammonium chloride (0.53 g, 0.0019 mol), andpalladium(II)acetate (0.094 g, 0.00042 mol). The reaction was stirred at120° C. for 17 h, cooled, EtOAc (200 mL) was added followed by NH₄OH(200 mL). The organic layer was separated, washed with brine, dried(Na₂SO₄) and concentrated to give solids. The solids were purified bysilica gel column chromatography using 80%EtOAc/MeOH as eluent to yield29 (0.25 g, 11%) as a tan solid. NMR was consistent for assignedstructure.

Compound (30)

NaNO₂ (5.3 g, 0.077 mol) was added to compound 29 (1.30 g, 0.0043 mol)in 12N HCl (14 mL) at ice bath temperatures. The reaction was stirred atice bath temperatures for 30 min then at room temperature for 2 h. Themixture was added to NH₄OH (75 mL), extracted with CHCl₃ (2×100 mL),separated, dried (Na₂SO₄) and concentrated. The residue was purified bysilica gel column chromatography using 80 CMA(CHCl₃:CH₃OH:NH₄OH/40:9:1):hexane:EtOAc (2:1:1) as the eluent to afford30 (0.35 g, 40%) as an orange oil. The HCl salt was prepared bydissolving the free base in ether and adding ethereal HCl to give solidswhich were crystallized from MeOH/EtOAc mixtures to yield 30 as a whitesolid: mp 120-122° C.; ¹H NMR (CDCl₃, free base) δ 1.51-1.69 (m, 6H),1.92 (m, 1H), 2.87 (m, 1H), 3.70 (m, 1H), 3.81 (m, 1H), 7.02 (s, 1H),8.39 (s, 1H). (C₁₂H₁₆Cl₂N₂ 1 1/4H₂O) C, H, N.

Experimental Procedures for Scheme 5 Shown in FIG. 16 Compound (32)

Compound 32 was prepared following the same procedures as shown inScheme 4 (FIG. 15) to yield 32 (31% from 31) as a white solid: mp 75-80°C.; ¹H NMR (CDCl₃, free base) δ _(—)1.62 (m, 6H), 1.92 (dd, 1H), 2.49(s, 3H, 2.86 (dd, 1H), 3.62 (m, 1H), 3.78 (t, 1H), 7.09 (d, 1H), 7.78(d, 1H). (C₁₂H₁₆Cl₂N₂ 3/4 H₂O) C, H, N.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-iodo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(33)

To a resealable reaction vessel containing DMF (16 mL) was added7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (796 mg, 4.08mmol), 2-amino-3,5-diiodopyridine (2.91 g, 8.41 mmol), Pd(OAc)₂ (55 mg,0.24 mmol), n-butyl ammonium chloride (284 mg, 1.02 mmol), and potassiumformate (690 mg, 8.2 mmol). The reaction tube was sealed under nitrogen,placed into an 85° C. oil bath, and let stir for 16 h. The reaction wasthen diluted with ethyl acetate, filtered through a celite pad, then theorganics were extracted with 1:1 NH₄H:H₂O (150 mL). The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 1:9 triethylamine:diethylether to yield7-tert-Butoxycarbonyl-2-exo-[5′-(3′-iodo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(0.108 g, 6%) as a colorless solid.

mp ° C.; ¹H NMR (CDCl₃) δ (ppm) 1.48 (s, 9H), 1.50-1.60 (m, 2H),1.70-1.90 (m, 4H), 2.62 (dd, J=5.3, 8.6 Hz, 1H), 4.34 (br s, 1H), 4.38(br s, 1H), 4.71 (br s, 2H), 7.69 (s, 1H, pyridyl CH), 8.09 (s, 1H,pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.3 (3C), 29.8, 31.3, 37.2, 43.6,55.4, 59.4, 80.2, 125.8, 142.3, 151.2, 154.0, 155.1.

2-exo-[5′-(3′-Iodo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (34)

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-iodo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(85 mg, 0.205 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated K₂CO₃ solution and extractedwith methylene chloride 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using (CHCl₃:CH₃OH:NH₄OH/45:9:1) as eluent to give2-exo-[5′-(3′-Iodo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane (45mg 70%) as a colorless solid.

mp 120-121° C.; ¹H NMR (CD₃OD) δ (ppm) 1.4-1.8 (m, 1H), 1.90 (dd, J 8.9,11.7 Hz, 1H), 2.66 (dd, J=5.4, 8.7 Hz, 1H), 3.30 (brs, 1 NH), 3.64 (brs, 1H), 3.68 (br s, 1H), 4.87 (s, 2H), 7.59 (s, 1H, pyridyl CH), 7.90(s, 1H, pyridyl CH); ¹³C NMR (CD₃OD) δ (ppm) 28.3, 30.3, 37.6, 44.6,57.5, 60.3, 122.5, 127.5, 143.4, 150.7, 157.3. Analytical Calculated forC₁₄H₁₄N₃I: C, 41.92; H, 4.48; N, 13.33; Found: C, 41.48; H, 4.49; N,12.81.

ADDITIONAL SYNTHETIC EXAMPLES7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene

A stirred solution of p-tolylsulfonylacetylene (30.11 g, 167.1 mmol) inN-tert-butoxycarbonyl-pyrrole (49.79 g, 298 mmol) was heated to 75° C.under nitrogen. After 5 days the tarry mixture was purified by flashchromatography over silica gel with 4:1 hexane:ethyl acetate to give7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(37.64 g, 64%) as a white solid.

mp 94-99° C.; ¹H NMR (CD₃OD) δ (ppm) 1.24 (s, 9H), 1.33 (s, 9H), 2.43(s, 3H), 5.15 (d, J=14.8 Hz, 1H), 5.36 (dd, J=1.8, 14.2 Hz, 1H), 6.90(m, 2H, alkenyl CH), 7.44 (d, J=7.2, 2H Aromatic), 7.67 (d, J=12.4, 1H,alkenyl CH), 7.76 (d, J=7.2 Hz, 2H Aromatic); ¹³C NMR (CD₃OD) δ (ppm)21.7, 28.2 (9C), 68.3, 69.2, 82.6, 129.3, 131.4, 137.0, 142.8, 144.0,144.4, 146.7, 153.7, 154.8, 155.5, 160.5; Analytical Calculated forC₁₈H₂₁O₄NS: C, 62.22; H, 6.09; N, 4.03; Found: C, 62.13; H, 6.09; N,3.96.

7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hept-2-ene(C3b)

To a stirred solution of nickel (II) acetate tetrahydrate (161 g, 647mmol) in ethanol (400 mL) was added dropwise a solution of sodiumborohydride (24.6 g, 1.54 mol) in ethanol (500 mL). This mixture wascooled to 0° C. and a solution of7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2,5-diene(44.49 g, 128 mmol) in THF (300 mL) was added. Concentrated HCl (100 mL)was next added and the mixture allowed to stir overnight. Afterquenching the reaction with sodium bicarbonate, the mixture was filteredover a celite pad and extracted several times with ethyl acetate. Thecombined organic layers were dried with sodium sulfate, concentrated,then purified by flash chromatography with 4:1 hexane:ethyl acetate togive7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2-ene(32.57 g, 73%) as a colorless solid.

mp 144-147° C.; ¹H NMR (CDCl₃) δ (ppm) 1.21 (s, 9H), 1.1-1.5 (m, 3H),1.9-2.1 (m, 2H), 2.44 (s, 3H), 4.76 (br s, 1H), 4.82 (br s, 1H), 7.05(s, 1H, alkenyl CH), 7.36 (d, J=7.2, 2H Aromatic), 7.81 (d, J=7.2 Hz, 2HAromatic); ¹³C NMR (CDCl₃) δ (ppm) 21.5, 24.5(2C), 27.7 (9C), 60.6,61.6, 80.6, 127.9 (2C), 129.9 (2C), 136.7, 144.7, 148.7, 154.7;Analytical Calculated for C₁₈H₂₃O₄NS: C, 61.87; H, 6.63; N, 4.01; Found:C, 61.91; H, 6.66; N, 4.08.

7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (C4b)

A 2.5% Na amalgam was prepared by adding sodium (15.1 g, 657 mmol)slices to mercury (56 mL, 3.77 mol). This amalgam was added in portionsto a vigorously stirring solution of NaH₂PO₄ (24.4 g, 203 mmol) andNa₂HPO₄ (28.9 g, 203 mmol) in a 1:1 tert-butanol:ethyl acetate mixture(100 mL). A solution of7-tert-Butoxycarbonyl-2-p-tolylsulfonyl-7-azabicyclo[2.2.1]-hepta-2-ene(14.22 g, 40.7 mmol) in a 1:1 tert-butanol-ethyl acetate mixture (200mL) was added to the stirring mixture at 0° C. After stirring for 24 hthe mixture was decanted into a separatory funnel and extracted withethyl acetate. The remaining mercury was washed thoroughly with ethylacetate. The combined organic layers were dried with sodium sulfate,concentrated, then purified by flash chromatography with 4:1hexane:ethyl acetate to provide7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]hept-2-ene (3-56 g, 45% basedon recovered starting material) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 0.97 (d, J=8Hz, 2H), 1.29 (s, 9H), 1.72 (d, J=9.2Hz, 2H), 4.53 (s, 2H), 6.08 (s, 2H, alkenyl CH); ¹³C NMR (CDCl₃) δ (ppm)23.19, 23.92, 27.99(3C), 59.35(2C), 79.36, 133.99, 134.77, 154.94.

5-Iodo-2-aminopyridine

To a mixture of 2-aminopyridine (47.2 g, 500 mmol), periodic aciddehydrate (23.0 g, 101 mmol), acetic acid (300 mL), water (70 mL), andsulfuric acid (9 mL) was added iodine crystals (51 g, 201 mmol). Themixture was allowed to heat at 80° C. for δ h. The reaction was thenpoured into a solution of Na₂S₂O₃ and extracted 3× with ether. The etherextracts were then washed with dilute NaOH and saturated NaCl, driedwith potassium carbonate, and concentrated. The residue was purified byflash chromatography using 4:1 hexane-ethyl acetate as eluent to provide5-Iodo-2-aminopyridine (32.6 g, 29%) as a colorless solid.

¹H NMR (CDCl₃) 8 (ppm) 4.45 (br s, 2H), 6.30 (d, J=8.4 Hz, 1H), 7.57(dd, J=2.4, 8.8 Hz, 1H), 8.17 (d, J=2.4 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm)77.7, 110. 8, 145.2, 153.7, 157.3.

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(C8)

To a resealable reaction vessel containing DMF (40 mL) was added7-tert-Butoxycarbonyl-7-azabicyclo[2.2.1]-hept-2-ene (2.317 g, 11.87mmol), 2-amino-5-iodopyridine (5.23 g, 23.8 mmol), Pd(OAc)₂ (142 mg,0.63 mmol), n-butyl ammonium chloride (830 mg, 2.98 mmol), and potassiumformate (1.96 g, 23.3 mmol). The reaction tube was sealed undernitrogen, placed into an 80° C. oil bath, and let stir for 16 h. Thereaction was then diluted with ethyl acetate, filtered through a celitepad, then the organics were extracted with 1:1 NH₄OH:H₂O (200 mL). Thecombined organic extracts were dried with magnesium sulfate,concentrated, then the residue was purified by flash chromatographyusing 1:2 hexane:ethyl acetate to yield7-tert-butoxycarbonyl-2-exo-[5′-(2′-Aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(3.101 g, 89%) as a colorless solid.

mp 119-120° C.; ¹H NMR (CDCl₃) δ (ppm) 1.37 (s, 9H), 1.39-1.53 (m, 2H),1.68-1.78 (m, 3H), 1. 86 (dd, J=9.2, 12.4 Hz, 1H, CH₂), 2.68 (dd, J=5.2,8.8 Hz, 1H, CH), 4.04 (br s, 1H), 4.20-4.44 (br s, 3H, amine+CH), 6.39(d, J=8.4 Hz, pyridyl CH), 7.35 (d, J=8.0 Hz, 1H pyridyl), 7.85 (s, 1Hpyridyl); ¹³C NMR (CDCl₃) δ (ppm) 28.2 (3C), 28.8, 29.8, 40.2, 45.0,55.6, 62.7, 79.4, 108.6, 131.2, 136.4, 146.5, 155.2, 156.9. AnalyticalCalculated for C₁₆H₂₂O₂N₃: C, 66.41; H,8.01; N, 14.52. Found: C, 66.51;H. 8.03; N, 14.56.

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane

2-exo-[5′-(2′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane (266 mg,1.27 mmol), BOC anhydride (400 mg, 1.83 mmol), DMAP (10 mg),triethylamine (0.100 mL), and methylene chloride (5 mL) were added to around bottom flask. Following 1 h of stirring, the reaction was pouredinto 1 M KHSO₄ and extracted with chloroform. The combined organiclayers were dried with sodium sulfate and concentrated. The cruderesidue was purified by flash chromatography using 3:1 hexane:ethylacetate to provide7-tert-Butoxycarbonyl-2-exo-[5′-(2′-Chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(245 mg, 62%) as an oil.

mp oil ° C.; ¹H NMR (CDCl₃) δ (ppm) 1.43 (s, 9H), 1.56 (m, 2H),1.75-1.90 (m, 3H), 1.99 (dd, J=9.0, 12.6 Hz, 1H), 2.86 (dd, J=5.0, 9.0Hz, 1H), 4.16 (s, 1H), 4.37 (s, 1H), 7.24 (d, J=8.3 Hz, 1H), 7.63 (dd,J=2.5, 8.3 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm)28.3, 28.8, 29.8, 40.0, 45.0, 66.0, 71.0, 79.9, 124.1, 137.2, 140.1,148.6, 149.3, 155.2.

5-Iodo-3-nitro-2-aminopyridine

A mixture of 2-amino-3-nitropyridine (5.0 g, 35.9 mmol), acetic acid (22mL), water (5 mL), sulfuric acid (0.650 mL), and HIO_(4×2)H₂O (1.7 g,7.5 mmol) was allowed to stir at 90° C. for 10 min. Iodine crystals (3.7g, 14.6 mmol) were added in portions. After stirring for 1 h, thereaction was poured into saturated sodium thiosulfate and extracted withethyl acetate. The organic layers were washed with 0.1 M NaOH andsaturated brine, dried with sodium sulfate, then evaporated to giveorange solid (7.5 g, 79% yield).

mp 213-215° C.; ¹H NMR (DMSO) δ (ppm) 8.03 (br s, 2H), 8.53 (d, J=2.0Hz, 1H), 8.58 (d, J=2.0 Hz, 1H); ¹³C NMR (DMSO) δ (ppm) 74.18, 127.92,141.31, 152.50, 160.88. Analytical Calculated for C₅H₄O₂N₃I: C, 22.66;H, 1.52; N, 15.86; Found: C, 22.88; H, 1.53; N, 15.69.

5-Iodo-2,3-diaminopyridine

5-Iodo-3-nitro-2-aminopyridine (2.0 g, 7.55 mmol), ethanol (7 mL), water(2 mL), and concentrated HCl (0.10 mL) were added to a 25 mL roundbottom flask and allowed to stir. Iron (4.8 g, 85.9 mmol) was added inportions to the reaction followed by heating at 100° C. for 30 min. Theiron was then removed and washed with ethanol over a fritted filterwhile the ethanol washings were concentrated under reduced pressure. Theresidue was purified by flash chromatography using 1:2 hexane:ethylacetate as eluent to give 5-Iodo-2,3-diaminopyridine as a light brownsolid (60%, 1.061 g).

mp 109-111° C.; ¹H NMR (DMSO) δ (ppm) 4.92 (br s, 2H), 5.60 (br s, 2H),6.93 (d, J=2.0 Hz, 1H), 7.39 (d, J=2.0 Hz, 1H); ¹³C NMR (DMSO) δ (ppm)77.40, 124.18, 132.26, 139.55, 147.66. Analytical Calculated forC₅H₆N₃l: C, 25.55; H, 2.57; N, 17.88; Found: C, 25.65; H, 2.53; N,17.84.

5-Iodo-3-nitro-2-chloropyridine

5-iodo-3-nitro-2-aminopyridine (2.511 g, 9.48 mmol) and concentrated HCl(20 mL) were stirred at room temperature for ten minutes. Sodium nitrite(13 g, 188 mmol) was then slowly added followed by CuCl (1.0 g, 10mmol). Stirring continued overnight. The mixture was poured into 1:1NH₄OH:H₂O, extracted with ethyl acetate, dried over sodium sulfate, thenconcentrated. The crude residue was purified by flash chromatographyusing 9:1 hexane:ethyl acetate to yield 5-iodo-3-nitro-2-chloropyridine(984 mg, 36%) as a colorless solid.

mp 77-79° C.; ¹H NMR (CDCl₃) δ (ppm) 8.50 (d, J=2.0 Hz, 1H), 8.82 (d,J=2.0 Hz, 1H); ¹³C NMR (DMSO) δ (ppm) 89.6, 141.7, 142.9, 144.9, 158.33.Analytical Calculated for C₅H₂O₂N₂lCl: C, 21.11; H, 0.71; N, 9.85;Found: C, 21.21; H, 0.71; N, 9.78.

5-Iodo-3-amino-2-chloropyridine

5-iodo-3-nitro-2-chloropyridine (230 mg, 0.809 mmol), ethanol (1 mL),water (6 drops), and concentrated HCl (0.020 mL) were stirred at roomtemperature for 10 min. Iron (500 mg, 8.95 mmol) was then added in smallportions and the reaction round bottom flask was placed into a 100° C.oil bath for 20 min. The iron was removed by filtration, washed withethanol, then the combined ethanol layers were concentrated underreduced pressure. The crude residue was purified by flash chromatographyusing 9:1 hexane: ethyl acetate to give 5-iodo-3-amino-2-chloropyridine(190 mg, 92%) as a colorless solid.

mp 129° C.; ¹H NMR (CDCl₃) δ (ppm) 4.15 (br s, 2H), 7.34 (d, J=2.0 Hz,1H), 7.96 (d, J=2.0 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 91.41, 129.67,136.31, 140.77, 143.90. Analytical Calculated for C₅H₄N₂lCl: C, 23.60;H, 1.58; N, 11.01; Found: C, 23-66; H, 1.52; N, 10.98.

2,3-Dichloro-5-iodopyridine

5-iodo-3-amino-2-chloropyridine (1.212 g, 4.76 mmol) and concentratedHCl (10 mL) were stirred at room temperature for ten minutes. Sodiumnitrite (5.3 g, 76.8 mmol) was then slowly added followed by CuCl (4.0g, 40.4 mmol). Stirring continued for 30 min. The mixture was pouredinto 1:1 NH₄OH:H₂O, extracted with ethyl acetate, dried over sodiumsulfate, then concentrated. The crude residue was purified by flashchromatography using 95:5 hexane:ethyl acetate to yield2,3-Dichloro-5-iodopyridine (913 mg, 70%) as a colorless solid.

¹HNMR(CDCl₃) δ (ppm) 8.08 (d,J=1.8 Hz, 1H), 8.49 (d,J=1.8 Hz, 1H); ¹³CNMR (CDCl₃) δ (ppm) 90.18, 131.46, 146.03, 148.81, 153.12. AnalyticalCalculated for C₅H₂NICl₂: C, 21.93; H, 0.74; N, 5.11; Found: C, 21.84;H, 0.74; N, 5.04.

2-Fluoro-3-nitro-5-iodopyridine

5-iodo-3-nitro-2-chloropyridine (0.624 g, 2.19 mmol), KF (265 mg, 58.1mmol), and DMF (3 mL) were stirred at 120 degrees Celsius for 24 h. Themixture was poured into saturated brine, extracted with ethyl acetate,dried over sodium sulfate, then concentrated. The crude residue waspurified by flash chromatography using 4-1 hexane:ethyl acetate to yield5-iodo-3-nitro-2-fluoropyridine (279 mg, 47%) as a colorless solid.

¹H NMR (CDCl₃) δ (ppm) 8.70 (s, 1H), 8.77 (d, J=7.7 Hz, 1H), ¹³C NMR(CDCl₃) δ (ppm) 86.66 (J_(CF)32 21.5 Hz), 144.24, 152.96, 156.97, 158.27(J_(CF)32 58 Hz). Analytical Calculated for C₅H₂N₂O₂Fl: C, 22.41; H,0.75; N, 10.45; Found: C, 22.57; H, 0.77; N, 10.24.

2-Bromo-3-nitro-5-iodopyridine

5-iodo-3-nitro-2-aminopyridine (5.6 g, 21.1 mmol) and concentrated HBr(60 mL) were stirred at room temperature for ten minutes. Sodium nitrite(11.7 g, 170 mmol) was then slowly added followed by CuBr (3.9 g, 27.2mmol). Stirring continued overnight. The mixture was poured into 1:1NH₄OH:H₂O, extracted with ethyl acetate, dried over sodium sulfate, thenconcentrated. The crude residue was purified by flash chromatographyusing 9:1 hexane:ethyl acetate to yield 5-iodo-3-nitro-2-bromopyridine(1.618 g, 23%) as a colorless solid.

¹H NMR (CDCl₃) δ (ppm) 8.34 (dd, J=0.8, 2.1 Hz, 1H), 8.72 (dd, J=0.8,2.0 Hz, 1H).

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-hydroxypyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide complex

To a heated 10 mL round bottom flask was added anhydrous DMF (1 mL),tert-butyl nitrite (0.120 mL, 1.0 mmol), and7-tert-Butoxycarbonyl-2-exo-[5′-(3′-Bromo-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(250 mg, 0.679 mmol). Stirring continued at 65° C. for 15 minutes. Thereaction was poured into a 1M solution of KHSO₄, extracted with ethylacetate 2×, concentrated, and purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to provide7-tert-Butoxycarbonyl-2-exo-[5′-(3′-bromo-2′-hydroxypyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide complex (237 mg, 79%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.38 (br s, 9H), 1.38-1.60 (m, 1H), 1.7-1.9 (m,5H), 2.62 (dd, J=4.7, 8.8 Hz, 1H), 2.89 (s, 3H), 2.96 (s, 3H), 4.08 (s,1H), 4.34 (s, 1H), 7.33 (d, J=1.8 Hz, 1H), 7.91 (s, 1H), 8.03 (s, 1H),13.33 (br s, 1H); ¹³C NMR (CDCl₃) δ (ppm) 28.3, 28.8, 29.5, 31.4, 36.4,39.6, 44.2, 56.0, 61.9, 80.0, 115.4, 125.2, 131.3, 143.9, 154.3, 160.8,162.5. HRMS (FAB+, nba/peg-600): m/z 369.0812 (M⁺+H, exact masscalculated for C₁₆H₂₂N₂O₃Br: 369.0812).

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-hydroxy-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide Complex

To a heated 10 mL round bottom flask was added anhydrous DMF (2.5 mL),tert-butyl nitrite (0.150 mL, 0.72 mmol), and7-tert-Butoxycarbonyl-2-exo[5′-(3′-phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(176 mg, 0.482 mmol). Stirring continued at 65° C. for 15 minutes. Thereaction was poured into a 1M solution of KHSO₄, extracted with ethylacetate 2×, concentrated, and purified by flash chromatography usingCHCl₃:CH₃OH:NH₄OH (45:9:1) as eluent to provide7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-hydroxypyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide complex (160 mg, 76%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.41 (br s, 9H), 1.38-1.60 (m, 2H), 1.7-2.0 (m,4H), 2.66 (dd, J=4.8, 8.1 Hz,: 1H), 2.87 (s, 3H), 2.94 (s, 3H), 4.13 (s,1H), 4.33 (s, 1H), 7.20 (d, J=2.3 Hz, 1H),7.25-7.45 (m, 2H), 7.68-7.75(m, 2H), 7.64 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 13.30 (br s, 1H); ¹³C NMR(CDCl₃) δ (ppm) 28.1, 28.6, 29.3, 31.2, 36.2, 39.3, 44.3, 55.6, 61.7,79.5, 124.1, 125.2, 127.4, 127.9(2C), 128.3(2C), 130.6, 130.7, 136.5,139.9, 154.9, 162.3, 163.0. HRMS (FAB+, nba): m/z 367.2019 (M⁺+H, exactmass calculated for C₂₂H₂₇N₂O₃: 367.2019).

2-exo-[5′-(2′-hydroxy-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptane(RTI-7527-29) Hydrochloride

7-tert-Butoxycarbonyl-2-exo-[5′-(2′-hydroxy-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptaneDimethylformamide complex (85 mg, 0.194 mmol) was dissolved in1,4-dioxane (3 mL). After adding a solution of 3M HCl (0.5 mL), thereaction was allowed to reflux for 30 min. The solvents were thenremoved under reduced pressure and the residue pumped overnight toprovide2-exo-[5′-(2′-hydroxy-3′-phenylpyridinyl)]-7-azabicyclo[2.2.1]-heptane1.5 Hydrochloride 1.75 Hydrate (87 mg, Quantitative) as a light brownsolid.

mp Decomposed >100° C.; Analytical Calculated forC₁₇H₂₃N₂O_(2.75)Cl_(1.5): C, 57.92; H, 6.58; N, 7.95; Found: C, 57.70;H, 6.67; N, 7.65.

7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane

A solution of7-tert-Butoxycarbonyl-2-exo-[5′-(3′-phenyl-2′-aminopyridinyl)]-7-azabicyclo[2.2.1]-heptane(264 mg, 0.722 mmol) in methylene iodide (5.0 mL) and t-butyl nitrite(2.0 mL) was allowed to stir at room temperature for 30 min. HI (0.030mL) was then added. After 24 h the reaction was decanted into 1:1NH₄OH:H₂O and then extracted with chloroform 3×. The combined organicextracts were dried with sodium sulfate, concentrated, then the residuewas purified by flash chromatography using 9:1 hexane:ethyl acetate aseluent to give2-exo-[5′-(3′-phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (61mg, 18%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.37 (s, 9H), 1.48-1.65 (m, 2H), 1.75-1.93 (m,3H), 2.01 (dd, J=9.0, 10.8 Hz, 1H), 2.87 (dd,J=4.9, 8.7 Hz, 1H), 4.21(br s, 1H), 4.37 (br s, 1H), 7.30-7.52 (m, 6H, pyridyl CH+phenyl CH),8.24 (s, 1H, pyridyl CH); ¹³C NMR (CDCl₃) δ (ppm) 28.2 (3C), 28.6, 29.6,40.2, 44.8, 55.5, 61.7, 79.8,119.3, 128.1 (2C), 128.3, 129.3 (2C),135.7, 140.7, 141.4, 143.8, 148.3, 154.8.

2-exo-[5′-(3′-phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(RTI-7527-27)

A solution of7-tert-Butoxycarbonyl-2-exo[5′-(3′-phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane(53 mg, 0.111 mmol) in methylene chloride (1.0 mL) and trifluoroaceticacid (1.0 mL) was allowed to stir at room temperature for 30 min. Thereaction was then decanted into a saturated NaHCO₃ solution andextracted with chloroform 3×. The combined organic extracts were driedwith sodium sulfate, concentrated, then the residue was purified byflash chromatography using 90 CMA as eluent to give2-exo-[5′-(3′-Phenyl-2-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (42mg, 99%) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.47-1.82 (m, 4H), 1.92 (dd,J=9.0,12.2 Hz, 1H),2.78 (dd, J=4.8, 8.6 Hz, 1H), 3.61 (br s, 1H), 3.78 (br s, 1H),7.31-7.48 (m, 5H), 7.60 (d, J=2.3 Hz, pyridyl 1 CH), 8.25 (d, J=2.3 Hz,pyridyl 1 CH); ¹³C NMR (CDCl₃) δ (ppm) 30.04, 31.33, 40.22, 44.47,56.37, 62.64, 119.10, 128.13 (3C), 129.32(2C), 135.98, 141.63 (2C),143.64, 148.59.

2-exo-[5′-(3′-phenyl-2′-iodopyridinyl)]-7-azabicyclo [2.2.1]-heptane(RTI-7527-27) Monohydrochloride

2-exo-[5′-(3′-Phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptane (37mg, 0.098 mmol) was dissolved in ether (1 mL) and then 1M HCl in ether(1 mL) was added dropwise. The reaction was allowed to stir for 15 minat room temperature. The solvent was removed under reduced pressure andthe remaining2-exo-[5′-(3′-Phenyl-2′-iodopyridinyl)]-7-azabicyclo[2.2.1]-heptaneHydrochloride Dihydrate was pumped overnight to give (41 mg, 93%) as acolorless solid.

mp 162-164° C.; Analytical Calculated for C₁₇H₂₂N₂O₂lCl. C, 45.50; H,4.94; N, 6.24; Found, C, 45.45; H, 4.71; N, 5.93.

2-Fluoro-5-iodo-3-aminopyridine

5-Iodo-3-nitro-2-fluoropyridine (1.739 g, 6.49 mmol), ethanol (13 mL),water (2 mL), and concentrated HCl (0.20 mL) were added to a 25 mL roundbottom flask and allowed to stir. Iron (3.6 g, 64.4 mmol) was added inportions to the reaction followed by heating at 80° C. for 30 min. Theiron was then removed and washed with ethanol over a fritted filterwhile the ethanol washings were concentrated under reduced pressure. Theresidue was purified by flash chromatography using 1:2 hexane:ethylacetate as eluent to give 5-Iodo-2-fluoro-3-aminopyridine as a colorlesssolid (53%, 0.821 g).

¹H NMR (CDCl₃) δ (ppm) 3.94 (br s, 2H), 7.36 (dd, J_(HF)=2.0. 9.8 Hz,1H), 7.70 (t, J=1.9 Hz, 1H); ¹³C NMR (CDCl₃) δ (ppm) 87.84, 131.43,140.21 (J_(HF)=13.3 Hz), 150.34, 154.05.

2-exo-[5′-(3′-{3″-Methoxyphenyl}-pyridinyl)]-7-azabicyclo[2.2.1]-heptane(RTI-7527-46)

2-exo-[5′-(3′{3″-Methoxyphenyl}-2′-chloropyridinyl)]-7-azabicyclo[2.2.1]-heptane(80 mg, 0.254 mmol) was dissolved in methanol (4 mL) inside aheavy-walled glass tube. Black 10% Pd/C (130 mg) was then added and 40psi of hydrogen was maintained over the solution. Three days later thesolvent was removed under reduced pressure and the residue purified byflash chromatography with 90 CMA to give2-exo-[5′-(3′-{3″-Methoxyphenyl}-pyridinyl)]-7-azabicyclo[2.2.1]-heptane(28 mg, 39% yield) as a colorless oil.

¹H NMR (CDCl₃) δ (ppm) 1.45-1.80 (m, 4H), 1.86 (s, 1H), 1.94 (dd, J=8.9,12.3 Hz, 1H), 2.87 (dd, J=5.1, 8.7 Hz, 1H), 3.65 (br s, 1H), 3.80 (br s,1H), 3.86 (s, 3H), 6.9-7.5 (m, 4H), 7.88 (s, 1H), 8.50 (s, 1H), 8.64 (s,1H); ¹³C NMR (CDCl₃) δ (ppm) 30.06, 31.32, 40.28, 45.47, 55.35, 56.51,62.77, 113.20, 113.23, 119.74 (2C), 129.97, 133.09, 136.22, 139.69,141.79, 145.97, 148.04.

RTI-7527-11

Epibatidine (0.70 g, 0.0034 mol) and paraformaldehyde (3.5 g) were mixedin formic acid (20 mL) and placed in a sealed glass vessel at 110° C.for 5 h. The reaction was cooled, diluted with water (200 mL), basifiedwith 50% NaOH and extracted with CH₂Cl₂. The organic layer wasseparated, dried (Na₂SO₄) and concentrated to give solids. The free basewas converted to its HCl salt (ether/etereal HCl) to afford 1 (0.23 g,23%) as a white solid: mp 180-184° C.; ¹H NMR (DMSO-d₆) δ 1.80-2.13 (m,5H), 2.32 (m, 1H), 2.51 (s, 3H), 3.42 (m, 1H), 4.05 (m, 1H), 4.29 (br s,2H), 4.40 (m, 1H), 7.50 (d, 1H), 7.93 (d, 1H), 8.48 (s, 1H). Anal.(C₁₂H₁₆CIN₂ 1 2/3 H₂O) C, H, N.

RTI-7527-54

To DMF (10 mL) in a closed reaction vessel was added norbornylene (1.70g, 0.018 mol), 2-amino-5-iodo-pyridine (7.9 g, 0.036 mol), KO₂CH (3.0 g,0.036 mol), tetrabutylammonium chloride (1.3 g, 0.0045 mol), andpalladium(II)acetate (0.26 g, 0.0012 mol). The reaction was stirred at105° C. for 64 h, cooled, EtOAc (300 mL) was added followed by NH₄OH(200 mL). The organic layer was separated, washed with brine, dried(Na₂SO₄) and concentrated to give an oil. The oil was purified by silicagel column chromatography using EtOAc as the eluent to give RTI-7527-54(1.8 g, 53%) as an oil.

The HCl salt was prepared by dissolving the free base in ether andadding ethereal HCl to give solids which were crystallized fromMeOH/EtOAc mixtures to afford a white solid: 196-197° C.; ¹H NMR (CDCl₃,base) δ 1.15-1.76 (m, 8H), 2.25 (m, 1H), 2.34 (m, 1H), 2.62 (m, 1H),6.44 (m, 1H), 7.29 (dd, 1H), 7.91 (s, 1H). (C₁₂H₁₇ClN₂) C, H, N.

RTI-7527-49

The HCl salt of RTI-7527-54 (1.36 g (0.0061 mol) was added to 12N HCl(22 mL) in an ice bath. The reaction was stirred at bath temperaturesfor 15 min then at room temperature for 70 min. The mixture was added toNH₄OH (100 mL) and CHCl₃ (100 mL). The organic layer was separated,dried (Na₂SO₄) and concentrated to give an oil. The oil was purified bysilica gel column chromatography using 80 CMA/EtOAc (1:1) as eluent togive RTI-7527-49 (0.30 g, 26%) as a beige solid: mp 123-124° C. A CHNsample was prepared by dissolving the free base in ether and addingethereal HCl to give a beige solid: mp 125-127° C; ¹H NMR (CDCl₃, base)δ 1.14-1.73 (m, 8H), 2.23 (s, 1H), 2.33 (s, 1H), 2.48 (m, 1H), 6.54 (d,1H), 7.15 (d, 1H), 7.37 (dd, 1H). (C₁₂H₁₆ClNO), C, H, N.

RTI-7527-18

Trifluoroacetic acid (2.0 mL, 0.026 mol) was added to7-tert-butoxycarbonyl-2-exo-[5′-(2′-hydroxypyridinyl)]-7-azabicyclo[2,2,1]-heptane(0.45 g, 0.0015 mol) in CH₂Cl₂(5 mL). The reaction was stirred at roomtemperature for 1 h then concentrated in vacuo. The residue was purifiedby silica gel column chromatography using 80 CMA as eluent to affordRTI-7527-18 (0.24 g, 84%) as an oil. The HCl salt was prepared bydissolving the free base in ether and adding ethereal HCl to give solidswhich were crystallized from MeOH/EtOAc mixtures to afford a beigesolid: 220-223° C.; ¹H NMR (MeOD, base) δ 1.89-2.16 (m, 5H), 2.43 (m,1H), 3.48 (m, 1H), 4.36 (m, 1H), 4.54 (m, 1H), 7.19 (d, 1H), 8.13 (s,1H), 8.27 (d, 1H). (C₁₁H₁₆Cl₂N₂O) C, H, N.

RTI-7527-55

Compound 23 (Scheme 3, FIG. 14) (0.60 g, 0.0019 mol) and ammoniumformate (0.36 g, 0.0057 mol) were added to MeOH (30 mL). The mixture wasdegassed with N₂ and 10% Pd/C (0.44 g) was added and the reaction wasstirred at reflux for 1 h. The mixture was cooled, filtered throughCelite and concentrated in vacuo. The residue was converted to its HClsalt (MeOH/ethereal HCl) and recrystallized from MeOH/EtOAc to afford 12(0.25 g, 50%) as a white solid: mp 252-255° C.; ¹H NMR (CDCl₃, freebase) δ 1.42 (m, 2H), 1.82 (m, 2H), 2.21 (m, 2H), 2.52 (s, 1H), 2.99 (m,2H), 3.32 (s, 1H), 6.82 (br s, 2H), 7.20 (m, 1H), 7.64 (d, 1H), 8.14,(d, 1H), 8.51 (s, 1H). Anal. (C₁₂H₁₈ClN₂) C, H, N.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

What is claimed is:
 1. A compound represented by formula (II):

wherein A₃ is —R, —N(R)₂, —C(═NR)N(R)₂, or —OR; each Q is, independently, C—X or N, with the proviso that at least one Q is N and at least one Q is C—X; each X is, independently, H, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, with the proviso that at least one X is represented by the formula:

 wherein each S is, independently, halogen, alkyl, alkenyl, alkynyl, phenyl, aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, or two S, taken together with the phenyl group to which they are bonded, form a 2-naphthyl group; and c is 1, 2, 3, 4 or 5; Y is a halogen; and each R is, independently, H, alkyl, alkenyl, alkynyl, aryl, or aralkyl; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1, wherein c is
 1. 3. The compound of claim 1, wherein c is
 2. 4. The compound of claim 1, wherein c is
 3. 5. The compound of claim 1, wherein two of said S, taken together with the phenyl group to which they are bonded, form a 2-naphthyl group.
 6. The compound of claim 1, wherein c is 1, 2, 3, 4, or 5, and at least one S is halogen, alkyl, alkenyl, alkynyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, wherein R and Y are as defined in claim
 1. 7. The compound of claim 1, wherein c is 1, 2, 3, 4, or 5, and at least one S is halogen, alkyl, or —NO₂.
 8. The compound of claim 1, wherein c is 1, 2, or 3, and at least one S is halogen, alkyl, or —NO₂.
 9. The compound of claim 1, wherein c is 1 or 2, and at least one S is halogen, alkyl, or —NO₂.
 10. The compound of claim 1, wherein at least one X is halogen or —NH₂.
 11. The compound of claim 1, wherein at least one X is halogen, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, wherein R is as defined in claim
 1. 12. The compound of claim 1, wherein A₃ is H or alkyl.
 13. The compound of claim 1, wherein A₃ is H.
 14. The compound of claim 1, wherein one Q is N.
 15. The compound of claim 1, wherein each X is independently selected from the group consisting of H, F, Cl, Br, I, CH₃, OH, NH₂, (CH₃)₂N, NHAc, CF₃SO₃, subject to said proviso.
 16. The compound of claim 1, wherein R is H, alkyl or benzyl.
 17. The compound of claim 1, wherein said alkyl group in the definition of R is represented by the formula —(CH₂)_(n)—Y, wherein Y is a halogen and n is an integer from 1 to
 8. 18. The compound of claim 1, wherein the compound is represented by formula (IIa):

wherein A₃ is as defined in claim 1; X₁, X₂, X₃ and X₄ are each, independently, H, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, wherein at least one of X₁, X₂, X₃, and X₄ is represented by said formula:

wherein S and c are as defined in claim 1; Y is as defined in claim 1; and R is as defined in claim
 1. 19. The compound of claim 18, wherein the compound is represented by formula (IIb):

wherein A₃ is as defined in claim 18; X₁, X₃ and X₄ are each, independently, H, halogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN; R is as defined in claim 18; Y is as defined in claim 18; S is as defined in claim 18; and c is as defined in claim
 18. 20. The compound of claim 19, wherein c is
 1. 21. The compound of claim 19, wherein c is
 2. 22. The compound of claim 19, wherein c is
 3. 23. The compound of claim 19, wherein two of said S, taken together with the phenyl group to which they are bonded, form a 2-naphthyl group.
 24. The compound of claim 19, wherein c is 1, 2, 3, 4, or 5, and at least one S is halogen, alkyl, alkenyl, alkynyl, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)2, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, wherein R and Y are as defined in claim
 19. 25. The compound of claim 19, wherein c is 1, 2, 3, 4, or 5, and at least one S is halogen, alkyl, or —NO₂.
 26. The compound of claim 19, wherein c is 1, 2, or 3, and at least one S is halogen, alkyl, or —NO₂.
 27. The compound of claim 19, wherein c is 1 or 2, and at least one S is halogen, alkyl, or —NO₂.
 28. The compound of claim 19, wherein at least one of X₁, X₃, and X₄ is halogen or —NH₂.
 29. The compound of claim 19, wherein at least one of X₁, X₃, and X₄ is halogen, —OH, —OR, —CH₂—CO₂R, —CO—R, —CO₂R, —N(R)₂, —NR—CO—R, —CO—N(R)₂, —NRCO₂R, —SO₃CF₃, —NO₂, —N₃, —CF₃, —CH═CHY, or —CN, wherein R is as defined in claim
 19. 30. The compound of claim 19, wherein A₃ is H or alkyl.
 31. The compound of claim 19, wherein A₃ is H.
 32. The compound of claim 19, wherein X₁, X₃, and X₄ are each hydrogen.
 33. The compound of claim 19, wherein R is H, alkyl or benzyl.
 34. The compound of claim 19, wherein said alkyl group in the definition of R is represented by the formula —(CH₂)_(n)—Y, wherein Y is a halogen and n is an integer from 1 to
 8. 35. The compound of claim 1, which is labeled with at least one labeling atom, wherein at least one atom in the compound is a member selected from the group consisting of ³H, ¹¹C, ¹⁴C, ³⁵S, ¹⁸F, ¹²³I, ¹²⁵I, and ¹³¹I.
 36. The compound of claim 35, wherein at least one atom in the compound is a member selected from the group consisting of ³H, ¹¹C, ¹⁸F, and ¹²³I.
 37. The compound of claim 35, wherein at least one X is ¹⁸F, ¹²³I, ¹²⁵I, or ¹³¹I, subject to said proviso.
 38. The compound of claim 35, wherein at least one X is a phenyl group substituted with one or more of ¹⁸F, ¹²³I, ¹²⁵I, or ¹³¹I.
 39. A method of treating Alzheimer's disease, comprising administering an effective amount of the compound of claim 1 to a patient in need thereof.
 40. A method of treating nicotine addiction, comprising administering an effective amount of the compound of claim 1 a patient in need thereof.
 41. A method of treating tobacco addiction, comprising administering an effective amount of the compound of claim 1 to a patient in need thereof.
 42. A method of binding neuronal nicotinic acetylcholine receptors in a subject, comprising administering an effective amount of the compound of claim 1 to the subject.
 43. The method of claim 42, wherein said receptors are α₄β₄ receptors. 